Copper nanoparticles and immunotherapy rapidly eliminate cancer cells – Pilot Study
The combination of the nanoparticles and immunotherapy made the tumours disappear entirely and, as a result, works as a vaccine for lung and colon cancer – the two types that were investigated in the study. To confirm their finding, the researchers injected tumour cells back into the mice. These cells were immediately eliminated by the immune system, which was on the lookout for any new, similar, cells invading the body.
#copper #cancer #immunotherapy
Hendrik Naatz, Bella B. Manshian, Carla Rios Luci, Vasiliki Tsikourkitoudi, Yiannis Deligiannakis, Johannes Birkenstock, Suman Pokhrel, Lutz Mädler, Stefaan J. Soenen. Model-Based Nanoengineered Pharmacokinetics of Iron-Doped Copper Oxide for Nanomedical Applications. Angewandte Chemie International Edition, 2020; DOI: 10.1002/anie.201912312
“From this, we conclude that lithium, given along the lines of this model, can help to heal the damage caused by radiotherapy, even long after it was caused,” says lead author Giulia Zanni, postdoctoral researcher at Columbia University and former PhD student in Klas Blomgren’s group at Karolinska Institutet.
#radiation #lithium #heal
Giulia Zanni, Shinobu Goto, Adamantia F. Fragopoulou, Giulia Gaudenzi, Vinogran Naidoo, Elena Di Martino, Gabriel Levy, Cecilia A. Dominguez, Olga Dethlefsen, Angel Cedazo-Minguez, Paula Merino-Serrais, Antonios Stamatakis, Ola Hermanson, Klas Blomgren. Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition. Molecular Psychiatry, 2019; DOI: 10.1038/s41380-019-0584-0
The energy-buffering function of creatine certainly goes beyond regulating CD8 T cells. In CrT-KO mice, we have observed the hyporesponsiveness of multiple immune cells in various mouse tumor models. It is also likely that creatine regulates immune reactions to multiple diseases beyond cancer, such as infections and autoimmune diseases (Riesberg et al., 2016). Studying the roles of creatine in modulating various immune cells under different health and disease conditions will be interesting topics for future research.
Stefano Di Biase, Xiaoya Ma, Xi Wang, Jiaji Yu, Yu-Chen Wang, Drake J. Smith, Yang Zhou, Zhe Li, Yu Jeong Kim, Nicole Clarke, Angela To, Lili Yang. Creatine uptake regulates CD8 T cell antitumor immunity. The Journal of Experimental Medicine, 2019; jem.20182044 DOI: 10.1084/jem.20182044
Strain of common cold virus could revolutionize treatment of bladder cancer
A strain of the common cold virus has been found to potentially target, infect and destroy cancer cells in patients with bladder cancer, a new study reports. No trace of the cancer was found in one patient following treatment with the virus.
#bladdercancer #cancer #coldvirus
Nicola E Annels, David Mansfield, Mehreen Arif, Carmen Ballesteros-Merino, Guy R Simpson, Mick Denyer, Sarbjinder S Sandhu, Alan Melcher, Kevin J Harrington, BronwYn Davies, Gough Au, Mark Grose, Izhar N Bagwan, Bernard A. Fox, Richard G Vile, Hugh Mostafid, Darren Shafren, Hardev Pandha. Viral targeting of non-muscle invasive bladder cancer and priming of anti-tumour immunity following intravesical Coxsackievirus A21. Clinical Cancer Research, 2019; clincanres.4022.2018 DOI: 10.1158/1078-0432.CCR-18-4022
Mannose impairs tumour growth and enhances chemotherapy
Mannose impairs tumour growth and enhances chemotherapy
Tumours use more glucose than normal, healthy tissues. However, it is very hard to control the amount of glucose in your body through diet alone. In this study, the researchers found that mannose can interfere with glucose to reduce how much sugar cancer cells can use*.
Pablo Sierra Gonzalez et al, Mannose impairs tumour growth and enhances chemotherapy, Nature (2018). DOI: 10.1038/s41586-018-0729-3
Tumor, tumours, cancer, mannose, d-mannose, sugar, glucose, energy
A team of scientists studied a well-known natural product, resveratrol, which is found in grapes and in red wine. While its chemopreventive properties against cancers affecting the digestive tract have been documented by previous studies, resveratrol has so far shown no effect on lung cancers. Thanks to nasal administration, the UNIGE team obtained very promising results in a study conducted in mice.
Aymeric Monteillier, Aymone Voisin, Pascal Furrer, Eric Allémann, Muriel Cuendet. Intranasal administration of resveratrol successfully prevents lung cancer in A/J mice. Scientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-32423-0
Resveratrol may protect against a mutant protein found in half of all malignant tumors
Resveratrol may protect against a mutant protein found in half of all malignant tumors
A Brazilian study shows the action of resveratrol on the inhibition of amyloid aggregates of mutant p53 protein, a mutation found in more than half of malignant tumors
Danielly C. Ferraz da Costa, Nathali P.C. Campos Ronimara A. Santos, Francisca Hildemagna Guedes-da-Silva, Mafalda Maria D.C. Martins-Dinis, Letícia Zanphorlin, Carlos Ramos, Luciana P. Rangel and Jerson L. Silva Resveratrol prevents p53 aggregation in vitro and in breast cancer cells Oncotarget. 2018; 9:29112-29122. https://doi.org/10.18632/oncotarget.25631
Patients that receive kidney transplants have an increased risk of an invasive form of skin cancer. It is unclear if donor tissue contributes to cancer formation. In this issue of the Journal of Clinical Investigation, Philippe Ratajczak and colleagues at INSERM demonstrate that donor tissue can lead to caner formation in transplant recipients. They examined tumor cells and transplant tissues from a small sample of kidney transplant patients that had subsequently developed skin squamous cell carcinoma (SCC). In one patient they identified the presence of skin tumor cells that were the same genotype as the donated kidney and contained a mutation in a known cancer-causing gene. Furthermore, cells with this mutation were present in kidney biopsy samples taken at the time of transplant. As Cai-Bin Cui and David Gerber from the University of North Carolina discuss in their accompanying commentary, this case study has important implications for cancer research and clinical care of transplant recipients.
TITLE: Human skin carcinoma arising from kidney transplant–derived tumor cells
The virus used in the vaccine that helped eradicate smallpox is now working its magic on liver cancer. A genetically engineered version of the vaccinia virus has trebled the average survival time of people with a severe form of liver cancer, with only mild, flu-like side effects.Thirty people with hepatocellular carcinoma received three doses of the modified virus – code-named JX-594 – directly into their liver tumour over one month. Half the volunteers received a low dose of the virus, the other half a high dose. Members of the low and high-dose groups subsequently survived for, on average, 6.7 and 14.1 months respectively. By contrast, trials several years ago showed that sorafenib, the best existing medication for this cancer, prolonged life by only three months.
Two of the patients on the highest viral dose were still alive more than two years after the treatment. “It’s a very substantial survival benefit,” says Laurent Fischer, president of Jennerex, the company in San Francisco developing the treatment under the trade name Pexa-Vec.
Besides shrinking the primary tumour, the virus was able to spread to and shrink any secondary tumours outside the liver. “Some tumours disappeared completely, and most showed partial destruction on MRI scans,” says David Kirn, head of the study at Jennerex. Moreover, the destruction was equally dramatic in the primary and secondary tumours.
“This clinical trial is an exciting step forward to help find a new way of treating cancers,” says Alan Melcher of the University of Leeds, UK, who was not involved in the study. “It helps demonstrate the cancer-fighting potential of viruses, which have relatively few side effects compared with traditional chemo or radiotherapy,” he says. “If it proves effective in larger trials, it could be available to patients within five years.”
The fact that the virus appears able to spread to secondary tumours suggests that simply injecting the virus into the bloodstream may be effective. A trial to compare this treatment with injecting the virus directly into a tumour is under way.
Targeted at cancer
The virus has had a gene coding for an enzyme called thymidine kinase snipped out. The enzyme enables the virus to recognise and infect dividing cells. By removing the gene, the virus’s developers have reduced the likelihood of healthy dividing cells being infected.
Instead, the virus exclusively attacks cancerous tissue, by targeting two genes that have increased activity in tumour cells. One genes is associated with an epidermal growth factor receptor, which stimulates the cancer to grow. The other is associated with a vascular endothelial growth factor, which enables the cancer to recruit its own blood supply. The virus reduces the activity of both genes, causing the infected cancer cell to wither and die.
What’s more, the virus carries extra genes to prod the body’s own immune system into action against the cancer. One produces granulocyte colony stimulating factor, a protein that encourages production of extra white blood cells at sites of infection. The other produces a protein not naturally found in humans, called Lac-Z, that earmarks infected cells for destruction.
Fischer says that to date, more than 200 people have received the virus, which has also shown promise against other types of cancer, including those of the kidney and skin. But he warns that not everyone sees a benefit. “We know why patients respond, but not why they don’t,” he says.
Changing bioelectric signals a key to halting tumor growth
MEDFORD/SOMERVILLE, Mass. (February 1, 2013) Biologists at Tufts University School of Arts and Sciences have discovered a bioelectric signal that can identify cells that are likely to develop into tumors. The researchers also found that they could lower the incidence of cancerous cells by manipulating the electrical charge across cells’ membranes.
“The news here is that we’ve established a bioelectric basis for the early detection of cancer,” says Brook Chernet, doctoral student and the first author of a newly published research paper co-authored with Michael Levin, Ph.D., professor of biology and director of the Center for Regenerative and Developmental Biology.
Levin notes, “We’ve shown that electric events tell the cells what to do. The voltage changes are not merely a sign of cancer. They control and direct whether the cancer occurs or not.”
Their paper, “Transmembrane Voltage Potential is an Essential Cellular Parameter for the Detection and Control of Tumor Development” will be published in the May 2013 issue of “Disease Models and Mechanisms” (available online on February 1).
Bioelectric signals underlie an important set of control mechanisms that regulate how cells grow and multiply. Chernet and Levin investigated the bioelectric properties of cells that develop into tumors in Xenopus laevis frog embryos.
In previous research, Tufts scientists have shown how manipulating membrane voltage can influence or regulate cellular behavior such as cell proliferation, migration, and shape in vivo, and be used to induce the formation or regenerative repair of whole organs and appendages. In this study, the researchers hypothesized that cancer can occur when bioelectric signaling networks are perturbed and cells stop attending to the patterning cues that orchestrate their normal development.
Tumor Cells Exhibit a Bioelectric Signature
The researchers induced tumor growth in the frog embryos by injecting the samples with mRNAs (messenger RNA) encoding well-recognized human oncogenes Gli1, KrasG12D, and Xrel3. The embryos developed tumor-like growths that are associated with human cancers such as melanoma, leukemia, lung cancer, and rhabdomyosarcoma (a soft tissue cancer that most often affects children).
When the researchers analyzed the tumor cells using a membrane voltage-sensitive dye and fluorescence microscopy, they made an exciting discovery. “The tumor sites had unique depolarized membrane voltage relative to surrounding tissue,” says Chernet. “They could be recognized by this distinctive bioelectric signal.
Changing Electrical Properties Lowers Incidence of Tumors
The Tufts biologists were also able to show that changing the bioelectric code to hyperpolarize tumor cells suppressed abnormal cell growth. “We hypothesized that the appearance of oncogene-induced tumors can be inhibited by alteration of membrane voltage,” says Levin, “and we were right.”
To counteract the tumor-inducing depolarization, they injected the cells with mRNA encoding carefully-chosen ion channels (proteins that control the passage of ions across cell membranes).
Using embryos injected with oncogenes such as Xrel3, the researchers introduced one of two ion channels (the glycine gated chloride channel GlyR-F99A or the potassium channel Kir4.1) known to hyperpolarize membrane voltage gradients in frog embryos. In both cases, the incidence of subsequent tumors was substantially lower than it was with embryos that received the oncogene but no hyperpolarizing channel treatment.
Experiments to determine the cellular mechanism that allows hyperpolarization to inhibit tumor formation showed that transport of butyrate, a known tumor suppressor, was responsible
The research was supported by grants from the National Institutes of Health (awards AR061988, AR055993) and the G. Harold and Leila Y. Mathers Charitable Foundation.
Chernet, B. T. and Levin, M. (2013). Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model. Dis. Model. Mech. 8 February [Epub ahead of print] doi:10.1242/dmm.010835
Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate, and professional programs across the university’s schools is widely encouraged.
A substance found in breast milk can kill cancer cells, reveal studies carried out by researchers at Lund University and the University of Gothenburg, Sweden.
Although the special substance, known as HAMLET (Human Alpha-lactalbumin Made LEthal to Tumour cells), was discovered in breast milk several years ago, it is only now that it has been possible to test it on humans. Patients with cancer of the bladder who were treated with the substance excreted dead cancer cells in their urine after each treatment, which has given rise to hopes that it can be developed into medication for cancer care in the future.
Discovered by chance
HAMLET was discovered by chance when researchers were studying the antibacterial properties of breast milk. Further studies showed that HAMLET comprises a protein and a fatty acid that are both found naturally in breast milk. So far, however, it has not been proven that the HAMLET complex is spontaneously formed in the milk. It is speculated, however, that HAMLET can form in the acidic environment of the babies´ stomachs. Laboratory experiments have shown that HAMLET kills 40 different types of cancer, and the researchers are now going on to study its effect on skin cancer, tumours in the mucous membranes and brain tumours. Importantly, HAMLET kills only cancer cells and does not affect healthy cells.
MU researcher finds that prostate tumor cells are more susceptible to treatment after being exposed to resveratrol, a compound found in grape skins and red wine
:Nicholl has discovered that a compound found in grape skins and red wine can make prostate tumor cells more susceptible to radiation treatment.
COLUMBIA, Mo. — Resveratrol, a compound found commonly in grape skins and red wine, has been shown to have several beneficial effects on human health, including cardiovascular health and stroke prevention. Now, a University of Missouri researcher has discovered that the compound can make prostate tumor cells more susceptible to radiation treatment, increasing the chances of a full recovery from all types of prostate cancer, including aggressive tumors.
“Other studies have noted that resveratrol made tumor cells more susceptible to chemotherapy, and we wanted to see if it had the same effect for radiation therapy,” said Michael Nicholl, an assistant professor of surgical oncology in the MU School of Medicine. “We found that when exposed to the compound, the tumor cells were more susceptible to radiation treatment, but that the effect was greater than just treating with both compounds separately.”
Cells contain very low levels of two proteins, perforin and granzyme B, which can function together to kill cells. However, both proteins need to be highly “expressed” to kill tumor cells. In his study, when Nicholl introduced resveratrol into the prostate tumor cells, the activity of the two proteins increased greatly. Following radiation treatment, Nicholl found that up to 97 percent of the tumor cells died, which is a much higher percentage than treatment with radiation alone.
“It is critical that both proteins, perforin and granzyme B, are present in order to kill the tumor cells, and we found that the resveratrol helped to increase their activity in prostate tumor cells,” Nicholl said. “Following the resveratrol-radiation treatment, we realized that we were able to kill many more tumor cells when compared with treating the tumor with radiation alone. It’s important to note that this killed all types of prostate tumor cells, including aggressive tumor cells.”
Resveratrol is present in grape skins and red wine and available over-the-counter in many health food sections at grocery stores. However, the dosage needed to have an effect on tumor cells is so great that many people would experience uncomfortable side effects.
VIDEO:University of Missouri scientists have found that resveratrol can make prostate tumor cells more susceptible to radiation treatment.
“We don’t need a large dose at the site of the tumor, but the body processes this compound so efficiently that a person needs to ingest a lot of resveratrol to make sure enough of it ends up at the tumor site. Because of that challenge, we have to look at different delivery methods for this compound to be effective,” Nicholl said. “It’s very attractive as a therapeutic agent since it is a natural compound and something that most of us have consumed in our lifetimes.”
Nicholl said that the next step would be to test the procedure in an animal model before any clinical trials can be initiated. Nicholl’s studies were published in the Journal of Andrology and Cancer Science. The early-stage results of this research are promising. If additional studies, including animal studies, are successful within the next few years, MU officials will request authority from the federal government to begin human drug development (this is commonly referred to as the “investigative new drug” status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for cancer.
COLUMBIA, Mo. – Previous studies have found that postmenopausal women who have taken a combined estrogen and progestin hormone replacement therapy have increased their risk of developing progestin-accelerated breast tumors. Now, University of Missouri researchers have found that curcumin, a popular Indian spice derived from the turmeric root, could reduce the cancer risk for women after exposure to hormone replacement therapy.
“Approximately 6 million women in the United States use hormone replacement therapy to treat the symptoms of menopause,” said Salman Hyder, the Zalk Endowed Professorship in Tumor Angiogenesis and professor of biomedical sciences in the College of Veterinary Medicine and the Dalton Cardiovascular Research Center. “This exposure to progestin will predispose a large number of post-menopausal women to future development of breast cancer. The results of our study show that women could potentially take curcumin to protect themselves from developing progestin-accelerated tumors.”
In the study, researchers found that curcumin delayed the first appearance, decreased incidence and reduced multiplicity of progestin-accelerated tumors in an animal model. Curcumin also prevented the appearance of gross morphological abnormalities in the mammary glands. In previous studies, MU researchers showed that progestin accelerated the development of certain tumors by increasing production of a molecule called VEGF that helps supply blood to the tumor. By blocking the production of VEGF, researchers could potentially reduce the proliferation of breast cancer cells. Curcumin inhibits progestin-induced VEGF secretion from breast cancer cells, Hyder said.
“Curcumin and other potential anti-angiogenic compounds should be tested further as dietary chemopreventive agents in women already exposed to hormone replacement therapy containing estrogen and progestin in an effort to decrease or delay the risk of breast cancer associated with combined hormone replacement therapy,” Hyder said.
The study, “Curcumin delays development of MPA-accelerated DMBA-induced mammary tumors,” has been accepted for publication in Menopause, a journal of the North American Menopause Society. It was coauthored by Hyder; Candace Carroll, graduate student of biomedical sciences; Cynthia Besch-Williford, associate professor of veterinary pathobiology in the MU College of Veterinary Medicine; and Mark Ellersieck, professor and researcher in the MU Experiment Station Statistics
Powdered turmeric has been used for centuries to treat osteoarthritis and other illnesses. Its active ingredient, curcumin, inhibits inflammatory reactions. A new study now shows that it can also inhibit formation of metastases. Prostate cancer is one of the most prevalent malignancies in the Western world, and is often diagnosed only after metastatic tumors have formed in other organs. In three percent of cases, these metastases are lethal. A research team led by PD Dr. Beatrice Bachmeier at LMU Munich has been studying the mode of action of a natural product that inhibits the formation of metastases. The compound is found in turmeric, a plant that has been used for medicinal purposes for thousands of years, and is a major ingredient of curry.
Bachmeier’s research centers on curcumin, the polyphenol responsible for the characteristic color of curry. Curcumin is well tolerated and is therefore, in principle, suitable both for prophylactic use (primary prevention) and also for the suppression of metastases in cases where an established tumor is already present (secondary prevention). In a previous study Bachmeier and her colleagues had demonstrated that the substance reduces statistically significantly the formation of lung metastases in an animal model of advanced breast cancer.
The new study was designed to investigate the efficacy of curcumin in the prevention of prostate cancer metastases, and to determine the agent’s mechanism of action. The researchers first examined the molecular processes that are abnormally regulated in prostate carcinoma cells. Breast and prostate cancers are often associated with latent or chronic inflammatory reactions, and in both cases, the tumor cells were found to produce pro-inflammatory immunomodulators including the cytokines CXCL1 und CXCL2.
The researchers went on to show that curcumin specifically decreases the expression of these two proteins, and in a mouse model, this effect correlated with a decline in the incidence of metastases. “Due to the action of curcumin, the tumor cells synthesize smaller amounts of cytokines that promote metastasis,” says Bachmeier. “As a consequence, the frequency of metastasis formation in the lungs is significantly reduced, in animals with breast cancer, as we showed previously, or carcinoma of the prostate, as demonstrated in our new study.”
Curcumin and chemoprevention
Bachmeier therefore believes that curcumin may be useful in the prevention of breast and prostate cancers – which are both linked to inflammation – and in reducing their metastatic potential. “This does not mean that the compound should be seen as a replacement for conventional therapies. However, it could play a positive role in primary prevention – before a full-blown tumor arises – or help to avert formation of metastases. In this context the fact that the substance is well tolerated is very important, because one can safely recommend it to individuals who have an increased tumor risk.”
A daily intake of up to 8g of curcumin is regarded as safe, and its anti-inflammatory properties have long been exploited in traditional oriental medicine. Men with benign hyperplasia of the prostate (BHP) are one possible target group for prophylaxis, as are women who have a family history of breast cancer. The agent might also be valuable as a supplement to certain cancer therapies. At all events, curcumin’s beneficial effects must first be confirmed in controlled clinical tests. Bachmeier is now planning such a trial in patients who suffer from therapy-resistant carcinoma of the prostate.
Colon cancer is one of the leading causes of death in Western countries. The role of n-3 and n-6 PUFAs in colorectal carcinoma cell growth has not been well studied. It is known that PGE2, generated from AA, is an important factor in the tumorigenesis of colorectal cancer. However, previous in vitro observations have led to uncertainty regarding a differential role of n-3 and n-6 PUFA for growth of tumor cells, as some findings are contradictory, and most studies have not addressed the effect of a changed n-3/n-6 PUFA ratio on cell proliferation.
A research article to be published on March 7, 2009 in the World Journal of Gastroenterology addresses this question. The research team around Piet Habbel and Karsten H. Weylandt from the Charité University Hospital in Berlin (Germany) and led by Jing X. Kang from the Massachusetts General Hospital in Boston (USA) used the LS-174T colon cancer cell line, for which several previous studies have shown an important role of PGE2 as growth promoting agent. The study showed differential effects of n-6 PUFA AA and n-3 PUFA DHA. While proliferation was promoted by AA, incubation with DHA reduced cell growth and viability. In addition, this study demonstrated that the n-3 PUFA DHA can directly suppress AA- as well as PGE2-induced colon cancer cell growth.
These results add evidence to the argument that the ratio of n-6/n-3 PUFA (and in particular the ratio of AA versus DHA) may be a critical determinant of proliferation and tumor growth in the colon, and that DHA supplementation can suppress tumor cell growth, even in the presence of high AA- and PGE2 levels. These results suggest that supplementation of DHA may be a powerful tool to counteract AA- and PGE2-promoted colon cancer cell growth that is associated with the predominant Western diet.
Reference: Habbel P, Weylandt KH, Lichopoj K, Nowak J, Purschke M, Wang JD, He CW, Baumgart DC, Kang JX. Docosahexaenoic acid suppresses arachidonic acid-induced proliferation of LS-174T human colon carcinoma cells. World J Gastroenterol 2009; 15(9): 1079-1084
PUBLISHED:06:40 EST, 8 October 2012| UPDATED:10:02 EST, 8 October 2012
Magnets that cause tumours to ‘self-destruct’ could be a revolutionary new weapon in the fight against cancer.
Scientists in South Korea have developed the method, which uses a magnetic field to trigger the cells to effectively kill themselves.
The researchers have demonstrated that the process works in bowel cancer cells and living laboratory fish.
They now plan to test the technique on a range of cancers to see if it can destroy other tumours.
Fighting cancer: The breakthrough treatment triggers the diseased cells to effectively commit suicide, blasting away the cancer from within.
Programmed cell death, or apoptosis, as it is known, is one of the body’s ways of getting rid of old, faulty or infected cells.
In response to certain signals, the doomed cell shrinks and breaks into fragments. These are then engulfed and consumed by amoeba-like immune cells.
But with cancer, this cell-death process often fails, so cells are allowed to keep dividing uncontrollably.
The new magnetic therapy involves creating tiny iron nanoparticles attached to antibodies – proteins produced by the body’s immune system when it detects harmful substances.
These iron nanoparticles then bind to the molecules on tumour cells.
When the magnetic field is applied, the molecules cluster together, automatically triggering the ‘death signal’.
The process raises the hope of new targeted treatments that could kill tumour cells resistant to the usual process of cell death.
Reducing the risk: Recent research found an estimated 22,000 cancer cases could be avoided by maintaining a healthy weight.
In the South Korean research, bowel cancer cells were exposed to the nanoparticles and placed between two magnets.
More than half the exposed cells were destroyed by magnetic activation, whereas no untreated cells were affected.
The research is published in the journal Nature Materials.
Henry Scowcroft, at Cancer Research UK’s science information manager, said: ‘This is fascinating but extremely preliminary research.
‘These Korean researchers have developed an antibody-based molecule that, when activated by a magnetic field, can cause cancer cells to die in highly artificial laboratory conditions and animal models.
‘There’s a long way to go before it’s ready to test in humans, but research like this shows just how ingenious scientists around the world are becoming in the quest to beat cancer.’
However, simply maintaining a healthy body weight could go a long way to preventing cancer occurring in the first place.
A report published last week by the World Cancer Research fund warned that more than 22,000 cases could be prevented every year.
Excess body weight raises the risk of a host of diseases including cancers of the pancreas, breast, bowel, oesophagus, kidney, womb and gall bladder.
However the rates of people dying from cancer are predicted to fall by 17 per cent in the UK by 2030, according to statistics released last month by Cancer Research UK.
For all cancers, 170 people in every 100,000 died from the disease in 2010. By 2030 it is predicted this will fall to 142 in every 100,000.
This is largely due to earlier diagnosis and improved treatments, but also reflects a reduction in smoking-related cancers leading to fewer deaths.
New research in an animal model suggests that a diet high in inorganic phosphates, which are found in a variety of processed foods including meats, cheeses, beverages, and bakery products, might speed growth of lung cancer tumors and may even contribute to the development of those tumors in individuals predisposed to the disease.
The study also suggests that dietary regulation of inorganic phosphates may play an important role in lung cancer treatment. The research, using a mouse model, was conducted by Myung-Haing Cho, D.V.M., Ph.D., and his colleagues at Seoul National University, appears in the first issue for January of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.
“Our study indicates that increased intake of inorganic phosphates strongly stimulates lung cancer development in mice, and suggests that dietary regulation of inorganic phosphates may be critical for lung cancer treatment as well as prevention,” said Dr. Cho.
Lung cancer is the number one cause of cancer deaths in the world and is also the most frequently diagnosed solid tumor. Non–small cell lung cancer (NSCLC) constitutes over 75 percent of lung cancers and has an average overall 35-year survival rate of 14 percent. Earlier studies have indicated that approximately 90 percent of NSCLC cases were associated with activation of certain signaling pathways in lung tissue. This study revealed that high levels of inorganic phosphates can stimulate those same pathways.
“Lung cancer is a disease of uncontrolled cell proliferation in lung tissue, and disruption of signaling pathways in those tissues can confer a normal cell with malignant properties,” Dr. Cho explained. “Deregulation of only a small set of pathways can confer a normal cell with malignant properties, and these pathways are regulated in response to nutrient availability and, consequently, cell proliferation and growth.
“Phosphate is an essential nutrient to living organisms, and can activate some signals,” he added. “This study demonstrates that high intake of inorganic phosphates may strongly stimulate lung cancer development by altering those (signaling) pathways.”
In the study, lung cancer-model mice were studied for four weeks and were randomly assigned to receive a diet of either 0.5 or 1.0 percent phosphate, a range roughly equivalent to modern human diets. At the end of the four-week period, the lung tissue was analyzed to determine the effects of the inorganic phosphates on tumors.
“Our results clearly demonstrated that the diet higher in inorganic phosphates caused an increase in the size of the tumors and stimulated growth of the tumors,” Dr. Cho said.
Dr. Cho noted that while a moderate level of phosphate plays an essential role in living organisms, the rapidly increasing use of phosphates as a food additive has resulted in significantly higher levels in average daily diets. Phosphates are added to many food products to increase water retention and improve food texture.
“In the 1990s, phosphorous-containing food additives contributed an estimated 470 mg per day to the average daily adult diet,” he said. “However, phosphates are currently being added much more frequently to a large number of processed foods, including meats, cheeses, beverages, and bakery products. As a result, depending on individual food choices, phosphorous intake could be increased by as much as 1000 mg per day.”
“Although the 0.5 percent was defined as close to ‘normal,’ the average diet today is actually closer to the one percent diet and may actually exceed it,” Dr. Cho noted. “Therefore, the 0.5 percent intake level is actually a reduced phosphate diet by today’s scale.”
Dr. Cho said future studies will help refine what constitutes a “safe” level of dietary inorganic phosphate, with recommendations that will be easily achievable in the average population.
“The results of this study suggest that dietary regulation of inorganic phosphates has a place in lung cancer treatment, and our eventual goal is to collect sufficient information to accurately assess the risk of these phosphates,” he said.
John Heffner, M.D., past president of the ATS, stated that this line of investigation in animals addresses the complex interactions between host factors and the environment that underlie cancer in man. “We know that only some patients who smoke develop lung cancer but the reasons for this varying risk are unknown. This study now provides a rationale for funding case-control studies in humans to determine the potential role of dietary phosphates in promoting cancer.”
By Charles Q. Choi Published September 27, 2012| MyHealthNewsDaily
Radiation therapy and chemotherapy aimed at killing cancer cells may have the undesirable effect of helping to create cancer stem cells, which are thought to be particularly adept at generating new tumors and are especially resistant to treatment, researchers say.
Past studies hint that cancer stem cells give rise to new tumors. Researchers suggest they are ultimately responsible for the recurrence of cancers and the dangerous spread of a cancer throughout the body. Scientists also have found that cancer stem cells are more likely than other cancer cells to survive chemotherapies and radiation therapies, probably becausetheir “stemness” allows them to self-replenish by repairing their damaged DNA and removing toxins.
The exact origin of cancer stem cells is debated. One possibility is that normal stem cells — which are valued for their ability to give rise to other cell types in the body — mutate to become cancerous. Another is that regular cancer cells somehow acquire stem cell properties.
The new study suggests regular cancer cells can indeed give rise to cancer stem cells, and that the radiation commonly used to treat cancer can trigger their stemness.
“Radiotherapy has been a standard treatment for cancer for so long, so we were quite surprised that it could induce stemness,” said study researcher Dr. Chiang Li, of Harvard Medical School in Boston.
The scientists exposed regular cancer cells to gamma-rays, one form of ionizing radiation. They found that under the conditions that normally foster stem cell growth, regular cancer cells formed balls of cells — a hallmark of cancer stem cells.
Additionally, analysis of these irradiated cancer cells revealed activity of genes linked with stem cell behaviors, according to the findings the scientists detailed online Aug. 21 in the journal PLoS ONE.
Chemotherapy may have similar effects, according to previous findings that Li and his colleagues detailed in July in the journal Cell Cycle.
“So radiation and chemotherapy not only might create cancer stem cells, any pre-existing cancer stem cells in a tumor were veryresistant to radiation and chemotherapy, so they remain as well,” Li said. “This could help explain why these therapies are sometimes not as effective as we might hope.”
Li cautioned these lab findings might not prove relevant in patients in real life. “This was all carried out in the petri dish,” he said. “There is a long way we have to go before we can be sure about its clinical implications for patients, if any.”
Still, this research suggests that if scientists find a way to inhibit stemness in cancers, radiation therapy and chemotherapy then might cleanly finish off tumors.
“There are lots of projects both in academia and industry right now to develop cancer stem cell inhibitors, although those are still in early stages,” Li said.
CINCINNATI—Exposure to bisphenol A (BPA) may reduce the effectiveness of chemotherapy treatments, say University of Cincinnati (UC) scientists.
The research study, led by UC’s Nira Ben-Jonathan, PhD, says that BPA—a man-made chemical found in a number of plastic products, including drinking bottles and the lining of food cans—actually induces a group of proteins that protect cancer cells from the toxic effects of chemotherapy.
The findings are reported in the journal Environmental Health Perspectives and appear online Oct. 8, 2008, ahead of print.
“Resistance to chemotherapy is a major problem for cancer patients, especially those with advanced or metastatic disease,” says Ben-Jonathan, a professor of cancer and cell biology at UC who has studied BPA for more than 10 years. “Finding out what contributes to that resistance can give us an idea of what to target in order to make chemotherapy as effective as possible.”
Researchers have suspected that BPA could play a role in cancer because of the chemical’s structural similarities to a cancer-promoting compound called diethylstilbestrol (DES). But Ben-Jonathan’s team found that BPA isn’t exactly mimicking the action of DES.
“BPA does not increase cancer cell proliferation like DES does,” she says. “It’s actually acting by protecting existing cancer cells from dying in response to anti-cancer drugs, making chemotherapy significantly less effective.”
Ben-Jonathan’s team studied human breast cancer cells, subjecting them to low levels of BPA consistent with levels found in the blood of human adults. The team found that BPA is acting in cancer cells similar to the way estrogen does—by inducing proteins that protect the cells from chemotherapy agents.
Estrogen’s protein-inducing action has been previously linked to chemotherapy resistance, but researchers have been unable to explain why such resistance still occurs in certain patients with less estrogen. Ben-Jonathan says her team’s research has important implications for this subgroup of patients.
“Patients with less circulating estrogen—post-menopausal women, for example—can also suffer from chemotherapy resistance,” she says. “Linking BPA to this problem gives us one more avenue to explore in terms of preventing chemotherapy resistance.”
“These data,” study authors write, “provide considerable support to the accumulating evidence that BPA is hazardous to human health.”
Coauthors include Elizabeth LaPensee, Sejal Fox and Traci Tuttle.
The study was funded by grants from the National Institutes of Health, the Department of Defense and the Susan G. Komen Breast Cancer Foundation.
The cancer and cell biology department at UC is part of a joint cancer program involving the UC College of Medicine, Cincinnati Children’s Hospital Medical Center and University Hospital. The collaborative initiative brings together interdisciplinary research teams of caring scientists and health professionals to research and develop new cures, while providing a continuum of care for children, adults and families with cancer.
DURHAM, N.C. – Because of the way solid tumors adapt the body’s machinery to bring themselves more oxygen, chemotherapy and radiation may actually make these tumors stronger.
“In a sense, these therapies can make the tumor healthier,” said Mark W. Dewhirst, D.V.M., Ph.D., professor of radiation oncology at Duke University Medical Center. “Unless the treatment is very effective in killing many if not most tumor cells, you are shooting yourself in the foot.”
Dewhirst and colleagues Yiting Cao, M.D., Ph.D., of Duke Pathology, and Benjamin Moeller, M.D., Ph.D. have introduced this counter-intuitive idea at recent conferences and in a review article featured in the June issue of Nature Reviews Cancer.
Radiation and chemotherapy do kill most solid tumor cells, but in the cells that survive, the therapies drive an increase in a regulatory factor called HIF1 (hypoxia-inducible factor 1), which cells use to get the oxygen they need by increasing blood vessel growth into the tumor. Solid tumors generally have low supplies of oxygen, Dewhirst explained and HIF1 helps them get the oxygen they need.
The review article concludes that blocking HIF1 would provide a clear mechanism for killing solid-tumor cells, particularly cells that are proving resistant to radiation or chemotherapy treatments.
As a part of this work, Dewhirst’s team has been studying the phenomenon of rising and falling oxygen levels in tumors, called cycling hypoxia. Oxygen levels have been found to naturally cycle up and down in individual blood vessels as well as large tumor regions. This instability in the tumor’s oxygen levels can increase HIF-1 production and cause radiation therapy to fail, Dewhirst said.
“It is my opinion that the whole tumor grows more aggressively because of this pulsation of oxygen at low levels,” Dewhirst said. “Most people thought cycling hypoxia was caused by temporary stoppage of blood flow in single blood vessel in tumors. In fact, however, oxygen levels cycle up and down virtually everywhere in the tumor, which is caused by fluctuations in blood flow rate. It has been a challenge to convince people of this.”
Dewhirst and colleagues have made movies of oxygen transport in a tumor of a living animal that show the oxygen levels cycle up and down significantly, pulsing in waves seen as color changes in the movies. (View these movies at the Nature Reviews Cancer site: http://www.nature.com/nrc/journal/v8/n6/suppinfo/nrc2397.html )
The Duke team argues that blocking HIF1 is the consistent answer to tumor growth problems. Blocking HIF1 activity interferes with the tumor’s ability to undergo glycolysis (energy production) in low-oxygen conditions, which blocks tumor growth, the authors wrote. Exactly how to accomplish chemotherapy or radiation treatment in the safest, most effective ways, in combination with HIF1 blockade, is still open for exploration, Dewhirst said.
For example, targeting HIF1 in the early stages of tumor growth, especially in very early cancer spread, may help, Dewhirst said. “For a woman who has had a primary breast tumor removed, and who is at high risk for cancer spread, this might be a situation in which you’d target HIF1,” he explained. “Blocking HIF1 makes sense during the early stages of angiogenesis, which is the accelerated phase of blood vessel formation. In this way, you could keep the early metastasis sites inactive and prevent them from growing.”
The Duke team has completed a phase I trial with a HIF1 inhibitor. “We are actively pursuing this clinically and will be moving this study into Phase 2,” Dewhirst said. “We are interested in other applications of HIF-1 inhibition in combination with radiation and chemotherapy for different diseases.”
Radiation therapy is one of the most widely used cancer treatments, but it often damages normal tissue and can lead to debilitating conditions. A class of drugs known as mammalian target of rapamycin (mTOR) inhibitors can prevent radiation-induced tissue damage in mice by protecting normal stem cells that are crucial for tissue repair, according to a preclinical study published by Cell Press in the September issue of the journal Cell Stem Cell.
“We can exploit the emerging findings for the development of new preventive strategies and more effective treatment options for patients suffering this devastating disease,” says senior study author J. Silvio Gutkind of the National Institute of Dental and Craniofacial Research.
In response to radiation therapy, cancer patients often develop a painful condition called mucositis—tissue swelling in the mouth that can leave these patients unable to eat or drink and force them to rely on opioid-strength pain killers. Radiation therapy may cause this debilitating condition by depleting normal stem cells capable of repairing damaged tissue.
In the new study, Gutkind and his team found that the mTOR inhibitor rapamycin protects stem cells taken from the mouths of healthy individuals (but not cancer cells) from radiation-induced death and DNA damage, dramatically extending the lifespan of these normal stem cells and allowing them to grow. Rapamycin exerted these protective effects by preventing the accumulation of harmful molecules called reactive oxygen species. Moreover, mice that received rapamycin during radiation treatment did not develop mucositis.
Because rapamycin is approved by the Food and Drug Administration and is currently being tested in clinical trials for the prevention and treatment of various types of cancer, the new findings could have immediate and important implications for a large proportion of cancer patients. “Mucositis prevention would have a remarkable impact on the quality of life and recovery of cancer patients and at the same time would reduce the cost of treatment,” Gutkind says. “Our study provides the basis for further testing in humans, and we hope that these findings can be translated rapidly into the clinic.”
Iglesias-Bartolome et al.: “mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis.”
Finkel et al.: “Relief with Rapamycin: mTOR Inhibition Protects against Radiation-Induced Mucositis”(In Translation Article
A research group of the University of Granadahas found out that maslinic acid, a compound present in the leaf and the olive skin wax extracted from alpeorujo (crushed olive pulp), has the capacity of preventing cancer as well as regulating apoptosis in carcinogenic processes.
Maslinic acid is a protease inhibitor that, among other features, has the capacity of regulating cell growth. It is useful for cancer treatment, as it allows to control the hyperplasia and hypertrophy processes, typical of this disease. The scientists of the UGRhave characterized for the first time maslinic acid action from the molecular point of view when it is applied to the development of tumour cells.
This work has been carried out by Ph D student Fernando Jesús Reyes Zurita, and directed by Professor José Antonio Lupiáñez Cara, of the department of Biochemistry and Molecular Biology I. According to them, the advantages of maslinic acid are three: Unlike other anti-carcinogenic products, highly cytotoxic, it is a natural compound and, therefore, less toxic. In addition, it is selective, this is, it only acts on carcinogenic cells, whose pH is more acid than usual. And lastly, it has a preventive nature, as it can inhibit cancer appearance in those cells with a higher predisposition to develop it.
For all types of cancer
Although the research group of Professor Lupiáñez Cara has analysed the effect of maslinic acid in the treatment of colon cancer, it can be used in different types of tumours. For the moment, their research works have been developed in colon carcinoma lines and transgenic mice, but they have not dismissed the possibility of applying them to humans in future.
Maslinic acid is a pentacyclic terpene which, besides being anti-carcinogenic, it has anti-inflammatory and antioxidant effects and can be found in high concentrations in olive skin wax. At present, the only production plant of this substance at a semi-industrial level in the whole world is at the Faculty of Sciences of the University of Granada.
‘Death panels’ are a bad idea. But asking hard questions about health care is not.
In his more than 35 years of practice, Dr. Lowell Schnipper has seen a lot of women die from breast cancer. A patient’s options start to dwindle by the time tumor cells set up outposts in the bones, lungs, and other organs, defying all attempts to keep them under control. But in June, when the government approved Perjeta, Schnipper had something new to offer. The drug is one of an innovative class of drugs known as “targeted therapies.”
As the chief of oncology at Beth Israel Deaconess Medical Center in Boston, Schnipper knew Perjeta was not a cure: added to a standard treatment with Herceptin—another targeted therapy that was hailed as a breakthrough in 1998—Perjeta gives the average woman only about six months more of calm before her disease starts to stir again. Given the limited benefit, the price was startling. For most women, a full course of the drug combination will cost $188,000—enough, he says, “to give anybody a cold sweat.”
Americans spent more than $23 billion last year for cancer drugs, more than we paid for prescriptions to treat anything else. But many oncologists are starting to question what we are getting in return for that bill, whether the war on cancer has become too much of a race to produce the next blockbuster. “In general, progress for cancer has been halting and slow,” says David Howard of the Department of Health Policy and Management at Emory University. So far, most new drugs offer only marginal extensions of life and few cures. Howard says new so-called breakthroughs “overpromise and underdeliver.” Consider the popularity of Avastin, a targeted drug approved for metastatic colon cancer in 2004. A recent study found that almost 70 percent of patients on chemotherapy were receiving Avastin within a year of its release. In clinical trials, the drug increased survival by about five months. The cost? About $10,000 a month.
Treating cancer has never been cheap, but today, the price of each new treatment seems to outpace the one before, with little bearing on its efficacy. According to figures from insurer United Healthcare, a standard cocktail of drugs for treating lung cancer used to run about $1,000 a month. Today’s regimens cost from more than $6,000 to almost $10,000—for about two more months of life. “There is no such thing as a cancer drug coming on the market that is some sort of regular drug price,” says Dr. Peter Bach of Memorial Sloan-Kettering Cancer Center in New York, who studies the impact of cancer costs on U.S. health care. “They’re all priced at spectacularly high levels.” Which leads to an unsettling question: how much is a little more time worth? Would you spend $50,000 for four more months? How about $15,000 for two weeks?
Of three frontiers in cancer treatment, targeted therapies like Perjeta are widely seen as the best hope for a cure. Traditional chemotherapy is notorious for side effects because it wields destruction indiscriminately throughout the body. Targeted therapies are designed to hit cancer cells only. Perjeta, for example, targets a protein produced in excess amounts in some breast cancers; Avastin hinders the ability of a tumor to form new blood vessels to feed itself.
Doctors envision the day when every patient will have therapy precisely matched to the genetic bull’s-eyes of their own cancers. The holdup has been that cancer has proven to be more genetically crafty than researchers once imagined. Scientists may build a drug to hit one target, but a tumor may also employ lots of yet-undiscovered genetic tricks to keep itself alive. Instead of a magic bullet, scientists now know that any particular tumor may need lots of magic bullets. With so many targets unknown, a lot of patients end up getting drugs that barely touch their cancers, which is why the effectiveness of many new drugs remains underwhelming.
Not that this keeps a drug from becoming a blockbuster. Patients with advanced cancer, and their physicians, are hungry for progress. As a result, almost all of the 10 bestselling cancer drugs are targeted therapies, many less than a decade old. All came on the market at thousands of dollars a month, a trend that continues today with gusto. The drug Afinitor, a daily pill, was approved in July for patients with breast cancer. It costs more than $200 a tablet. But price rarely matters to patients or even doctors, says Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans. “People have already been told there is no cure for their disease,” he says. “Every increment, every improvement, gives hope, and when options are extremely limited, we all focus on the positive possibilities.”
In addition to targeted therapies, drugs have come on the market that can spur the body’s own immune cells to lead the charge. Significant hurdles have hindered this kind of treatment for years. But they are finally being overcome. The prostate cancer drug Provenge, which came on the market in 2010, was the first immune-therapy drug to gain governmental approval. It was followed the next year by Yervoy, when approved the only drug ever shown to extend survival in advanced melanoma. Men with a common kind of advanced prostate cancer who used Provenge lived an average of four months longer than the comparison group; patients on Yervoy got an average of 3.6 months. The gains are modest, but not the cost. When Sartor learned Provenge would run $93,000 per patient, “I was stunned,” he says. And even that was cheaper than Yervoy, which appeared the following year at $120,000 for four injections. He predicts the pricing of immune therapies may be seen as “a watershed moment” in the debate over health-care costs.
The third area of touted breakthroughs has been in radiation, most recently by using protons instead of traditional X-rays to kill cancer cells. It’s a controversial undertaking: many doctors believe that protons offer better precision, able to get rid of tumors without collateral damage to nearby healthy tissues. But whether protons can treat with fewer side effects than traditional radiation is, to date, a matter of debate for almost all but pediatric and certain neurological tumors.
As with new drugs, proton-beam radiation is expensive—it can run roughly twice as much as the current state-of-the-art form of radiation that uses X-rays. In the case of proton beams, much of the cost has to do with building a cyclotron to harvest the protons—a construction project that can cost upwards of $150 million. In 2001 just three centers in the country offered proton treatment, but that number is now up to 10, with a half dozen more planned. About three quarters of the proton patient population covered by Medicare are men with prostate cancer, which, because of the length of their therapy, are the most lucrative to treat.
Why do new drugs cost so much? Pharmaceutical companies say it’s payment for scientific creativity, that high prices are necessary to recover the expense of developing and manufacturing their products and to encourage more research. A spokeswoman for Bristol-Myers Squibb, which makes Yervoy, says the cost of drugs is “based on a number of factors, including the value they deliver to patients, the scientific innovation they represent, and the cost to develop them.” Part of the price is also an investment in drug discovery. “We look at not only the past research and development, but development in the future,” says Krysta Pellegrino, a spokeswoman for Genentech, which developed Perjeta.
That said, many cancer experts remain skeptical of the notion that drug companies are simply passing along the cost of doing business and funding the incubation of new drugs. In 2004 researchers tried to test the relationship between a drug’s development and its final asking price. In the Journal of Clinical Oncology, the scientists concluded “that the drug companies are not pricing their drugs to recuperate losses associated with research and development, marketing, and operating prices, but rather [the average wholesale price] depends on what the market itself can bear.”
“It’s a marketplace where the seller has all of the control,” says Bach, from Memorial Sloan-Kettering, because private insurance companies and Medicare—the largest purchasers of drugs—are powerless to bargain for a less expensive deal. “Prices are high because they can be,” Bach says. As one doctor observed, “we are always paying for a Ferrari but often getting a Ford.” The occasional Ferrari does exist. The targeted drug Gleevec, which treats certain forms of leukemia and intestinal tumors, has allowed patients to live for years with their cancer in check.
But while the track record for some new treatments is expected to improve, Dr. Otis Brawley, chief medical and scientific officer of the American Cancer Society, says that in most cases, “new cancer treatments cost an awful lot of money, and there is usually a very small incremental benefit.” Brawley, author of How We Do Harm: A Doctor Breaks Ranks About Being Sick in America, likes to cite the case of Tarceva, a targeted therapy approved for pancreatic cancer in 2005 to piggyback on the traditional drug gemcitabine. “The median survival of Tarceva and gemcitabine compared to gemcita-bine alone was 14 to 16 days greater. Seven months versus seven and a half months.” A 2007 analysis in the Journal of Clinical Oncology determined that those extra days add around $15,000 to the cost of care. “Instead of talking about rationing care,” Brawley says, “we need to talk about rational use of care.”
If new cancer treatments continue to push the boundaries of affordability, Americans will eventually be forced into dilemmas we have largely postponed. Innovative cancer treatments, says Emory’s Howard, “really symbolize the tradeoff that we face between improving health and saving money. At some point, society—including employers, the government, patients, and clinicians—have to make a tradeoff. I think if these drugs cured the disease, which none of them do, then no one would be questioning these prices. But we are seeing very high cost for relatively little return in patient benefit and survival.”
Other countries already consider a treatment’s effectiveness in national discussions about whether to pay for it. For example, this summer in Israel, a panel of radiation oncologists advised the Israeli Ministry of Health that, because of the unproven benefits, spending public money on proton-beam treatment is not yet warranted. “We can’t say it is a justifiable expense,” says Dr. Abraham Kuten, director of oncology at Rambam Medical Center in Haifa. The United Kingdom affirmed in July, for the second time, that it will not cover Avastin for advanced breast cancer. Australia, which has one of the world’s highest incidences of melanoma, decided in March that the benefits of Yervoy are not worth the cost to the country’s national health-care system; it based its decision on an independent government advisory committee, which cited the questionable benefit to patients and the drug’s “uncertain clinical place in therapy.”
Then there is the United States, where wider access to drugs may be one of the reasons our cancer survival times rank among the highest worldwide. But the question is how long we can afford what we’re getting. “I think we are the only industrialized country that doesn’t look at the cost balanced somehow with effectiveness in making decisions about drugs,” says Dr. Thomas Smith of the Sidney Kimmel Comprehensive Cancer Center in Baltimore. “What we have now are a bunch of blockbuster-ette drugs that give a little bit of benefit. If you’re that person, it could be a really big benefit to have three extra months before your disease starts growing again, but as a society we simply can’t pay for that for everybody.”
Yet aside from academics and insurance-company executives, few Americans are willing to consider the price of time, says Dr. Lee Newcomer, senior vice president for oncology at United Healthcare. This means that the government sinks further into debt, and insurance companies keep raising premiums to keep up. “If we’re going to continue to have a sustainable health system, we have to talk about that as a society. In 15 years, you will have to earn the equivalent of a year’s salary today to pay your health-insurance premiums,” he says. “We’re going to have to have the discussion.”
Laura Beil is an independent journalist based in Dallas
Triphala churna (THL) is a combination of three fruits that has been used for many years in India for the treatment of various diseases. There are now reports which indicate that THL can inhibit growth of malignant tumors in animals. However, the mechanisms by which THL mediates its anti-tumor actions are still being explored. Because vascular endothelial growth factor-A (VEGF) induced angiogenesis plays a critical role in the pathogenesis of cancer, we therefore investigated whether tumor inhibitory effects of THL or its active constituents are through suppression of VEGF actions. We herein report that THL and chebulinic (CI) present in THL can significantly and specifically inhibit VEGF induced angiogenesis by suppressing VEGF receptor-2 (VEGFR-2) phosphorylation. These results are of clinical significance as these inexpensive and non-toxic natural products can be used for the prevention and treatment of diseases where VEGF induced angiogenesis has an important role
Results and Discussion
There are now studies which indicate the therapeutic efficacies of THL in tumor bearing animals –. However, there is still no report indicating the effects of THL on VEGF induced angiogenesis –. We at first determined whether single oral dose of 100 mg/kg of THL could inhibit VEGF (250 ng) mediated angiogenesis in vivo in a well established mouse matrigel plug assay model –. This dose of THL was particularly selected as this dose demonstrated the highest efficacy in human malignant tumor bearing mice . In addition, we also did not observe any significant changes in the complete blood count, hepatic enzymes, cholesterol, blood sugar, blood urea nitrogen (BUN) and serum creatinine level with this dose of THL in mice when compared to normal controls (data not shown). On day 8, THL untreated plugs containing VEGF appeared dark red, Masson’s trichrome staining (endothelial cells stain red and the matrigel stain blue) and CD31 immunostaining demonstrated higher levels of endothelial cells in these VEGF containing THL untreated plugs (Fig. 2 A–D). In contrast, on Day 8, plugs containing VEGF removed from animals treated with THL for 7 days were pale in color and the endothelial cells were also significantly less in numbers (Fig. 2A–D). Similar results were observed in control plugs without VEGF removed from animals untreated with THL (Fig. 2A–D). These data confirmed that oral administration of THL could significantly inhibit VEGF induced angiogenesis in vivo.
Furthermore in vitro studies have indicated the anti-VEGF actions of GA and EA, two constituents of THL , . Since the bioavailability of these two compounds following ingestion of either fruits containing these two acids or in pure forms is poor , , , ,  and because we had observed significant suppression of VEGF induced angiogenesis following oral administration of THL in our in vivo model (Fig. 2), we therefore examined the plasma level of another major constituent of THL, CI following oral feeding of mice with THL. The plasma concentration of CI reached to 1952.67 ng/ml (2.04 μM) at 20 min after gavaging the mice with a single dose of THL (100 mg/kg) containing 6.8 mg of CI as detected by LC-MS/MS.
Because VEGF mediates its angiogenic actions by stimulating proliferation, migration, tube formation and endothelial cell permeability –, therefore in order to investigate whether THL could specifically inhibit these functions of VEGF in endothelial cells, we initially determined the non-toxic concentration of THL to be used for our in vitro experiments in HUVEC by examining the cytotoxic effects of various concentrations of THL (20–80 μg/ml) that were previously reported to inhibit tumor cell growth in vitro, , . In addition, we also determined the effect of 2 μM of CI on the viability of HUVEC as this concentration of CI was detected in the plasma of mice after orally feeding them with the VEGF inhibitory dose of THL (100 mg/kg). Our results indicated 40 μg/ml of THL to be the highest non-toxic concentration of THL and 2 μM CI had no effect on cell viability (Fig. 3A, B). Accordingly, we selected 40 μg/ml of THL and 2 μM of CI for further in vitro experiments.
We next examined the effects of non-toxic concentration of THL (40 μg/ml) and CI (2 μM) on VEGF induced proliferation, migration, tube formation and permeability in HUVEC. Our results indicated significant inhibition of VEGF (20 ng/ml) induced proliferation (Fig. 3 C, D), migration (Fig. 4 A–D) and tube formation (Fig. 5A–D) by these cells after treatment with THL or CI. In addition, THL and CI also significantly inhibited VEGF induced permeability in HUVEC (Fig. 5E). It is to be noted here that THL (40 μg/ml) or CI (2 μM) alone had no effects on proliferation, wound healing, tube formation and permeability of the endothelial cells (data not shown).
Furthermore as these actions of VEGF is mediated mainly through its VEGFR-2 –, therefore to elucidate the molecular mechanisms by which THL or CI inhibited VEGF functions, we investigated the effects of THL (40 μg/ml) and CI (2 μM) on VEGF (20 ng/ml) induced VEGFR-2 phosphorylation in HUVEC. Our results demonstrated that THL or CI significantly inhibited VEGF induced phosphorylation of VEGFR-2 (Fig. 5F).
Since our previous in vitro data suggested that THL and CI could significantly inhibit the important steps of VEGF induced angiogenesis (Fig. 3, 4, 5), therefore, we determined the effects of THL (40 μg/ml) and CI (2 μM) on VEGF mediated angiogenesis in CAM assay , , . All observations were made on Day 4 after addition of these compounds. There was no evidence of angiogenesis or inflammation on addition of the vehicle (PBS) in which THL or CI were dissolved (Fig. 6A, E). However, striking angiogenesis was evident after exposure to 250 ng of VEGF (Fig. 6B, E). On the contrary, significant inhibition of VEGF induced angiogenesis was observed following exposures to 40 μg/ml of THL or 2 μM of CI (Fig. 6C, D, E). THL or CI alone did not induce any inflammation nor had any effects on blood vessel formation (data not shown).
Taken together our results for the first time demonstrated that THL or CI present in THL can significantly inhibit VEGF induced angiogenesis via suppression of VEGFR-2 actions. Moreover unlike the other constituents of THL such as GA and EA, the plasma level of CI reached considerably after oral intake of THL and this level of CI in turn could significantly and specifically inhibit the actions of VEGF in vitro. These results thus suggest that CI present in THL mediate the anti-VEGF effects of THL in vivo and is also a potent inhibitor VEGF functions. However, there may be other untested constituents of THL, which may also possess anti-VEGF activities.
Finally, VEGF mediated neovascularization plays an important pathogenic role in various diseases –. The presently available anti-VEGF drugs not only have serious toxicities, but are also very expensive –. This necessitates development of newer and effective non-toxic and inexpensive anti-VEGF agents. Our present study suggests that THL or CI may fulfill this promise in future
A commercially available nutrition drink reduces the growth of tumors in a mouse model of human prostate cancer by 25 percent in two weeks, according to researchers from the University of Sydney. The drink, Blueberry Punch, is a mixture of plant-based chemicals – phytochemicals – known to have anti-cancer properties.
“While individual phytochemicals are successful in killing cancer cells, we reasoned that synergistic or additive effects are likely to be achieved when they are combined.”
Singh and her colleagues studied the effect of the beverage on both cancer cell cultures and in mouse models that mimic human prostate cancer. After 72 hours of exposure to increasing concentrations of Blueberry Punch, prostate cancer cells showed a dose-dependent reduction in size and viability when compared with untreated cells, Singh says. After feeding mice a 10 percent solution of the punch for two weeks, the tumors in the test mice were 25 percent smaller than those found in mice that drank only tap water.
Based on these results, the researchers believe Blueberry Punch is now ready for human prostate cancer trials. Because Blueberry Punch is a food product rather than a drug, it is unlikely to have adverse reactions or side effects assuming that the individual is tolerant to all ingredients, Singh says. “The evidence we have provided suggests that this product could be therapeutic, although it requires clinical validation,” Singh said
A nondisease-causing virus kills human breast cancer cells in the laboratory, creating opportunities for potential new cancer therapies, according to Penn State College of Medicine researchers who tested the virus on three different breast cancer types that represent the multiple stages of breast cancer development.
Adeno-associated virus type 2 (AAV2) is a virus that regularly infects humans but causes no disease. Past studies by the same researchers show that it promotes tumor cell death in cervical cancer cells infected with human papillomavirus. Researchers used an unaltered, naturally occurring version of AAV2 on human breast cancer cells.
“Breast cancer is the most prevalent cancer in the world and is the leading cause of cancer-related death in women,” said Samina Alam, Ph.D., research associate in microbiology and immunology. “It is also complex to treat.”
Craig Meyers, Ph.D., professor of microbiology and immunology, said breast cancer is problematic to treat because of its multiple stages.
“Because it has multiple stages, you can’t treat all the women the same. Currently, treatment of breast cancer is dependent on multiple factors such as hormone-dependency, invasiveness and metastases, drug resistance and potential toxicities. Our study shows that AAV2, as a single entity, targets all different grades of breast cancer.”
Cells have multiple ways of dying. If damage occurs in a healthy cell, the cell turns on production and activation of specific proteins that allow the cell to commit suicide. However, in cancer cells these death pathways are often turned off, while the proteins that allow the cell to divide and multiply are stuck in the “on” position.
One way to fight cancer is to find ways to turn on these death pathways, which is what researchers believe is happening with the AAV2 virus. In tissue culture dishes in the laboratory, 100 percent of the cancer cells are destroyed by the virus within seven days, with the majority of the cell death proteins activated on the fifth day. In another study, a fourth breast cancer derived cell line, which is the most aggressive, required three weeks to undergo cell death
“We can see the virus is killing the cancer cells, but how is it doing it?” Alam said. “If we can determine which viral genes are being used, we may be able to introduce those genes into a therapeutic. If we can determine which pathways the virus is triggering, we can then screen new drugs that target those pathways. Or we may simply be able to use the virus itself.”
Research needs to be completed to learn how AAV2 is killing cancer cells and which of its proteins are activating the death pathways.
According to Meyers, the cellular myc gene seems to be involved. While usually associated with cell proliferation, myc is a protein also known to promote cell death. The scientists have observed increased expression of myc close to the time of death of the breast cancer cells in the study. They report their results in a recent issue of Molecular Cancer.
AAV2 does not affect healthy cells. However, if AAV2 were used in humans, the potential exists that the body’s immune system would fight to remove it from the body. Therefore, by learning how AAV2 targets the death pathways, researchers potentially can find ways to treat the cancer without using the actual virus.
In ongoing studies, the Penn State researchers have also shown AAV2 can kill cells derived from prostate cancer, methoselioma, squamous cell carcinoma, and melanoma. A fourth line of breast cancer cells – representing the most aggressive form of the disease – was also studied in a mouse breast tumor model, followed by treatment with AAV2. Preliminary results show the destruction of the tumors in the mice, and researchers will report the findings of those mouse studies soon.
Other researchers on this project are Brian S. Bowser and Mohd Israr, Department of Microbiology and Immunology; Michael J. Conway, Section of Infection Diseases, Yale School of Medicine; and Apurva Tandon, Department of Microbiology, Immunology and Pathology, Colorado State University.
The Pennsylvania Department of Health, Breast and Cervical Cancer Initiative supported this research. The researchers have filed for a U.S. patent on this work
The lab test on one type of human skin cancer showed 40 per cent of tumours disappeared after a month of treatment, while an additional 30 per cent shrank.
Dr Christine Dufès, a senior lecturer at the Strathclyde Institute of Pharmacy and Biomedical Sciences, who led the research, said: “These are very encouraging results which we hope could pave the way for new and effective cancer treatments.
“When we used our method, the green tea extract reduced the size of many of the tumours every day, in some cases removing them altogether.
“By contrast, the extract had no effect at all when it was delivered by other means, as every one of these tumours continued to grow.
“This research could open doors to new treatments for what is still one of the biggest killer diseases in many countries.”
She added: “I was expecting good results, but not as strong as these.”
Dr Dufès said population studies had previously indicated that green tea had anti-cancer properties, and scientists had since identified the active compound as epigallocatechin gallate.
But the Strathclyde researchers were the first to delivery it in high enough doses to tumours to have an effect.
She explained: “The problems with this extract is that when it’s administered intravenously, it goes everywhere in the body, so when it gets to the tumours it’s too diluted.
“With the targeted delivery system, it’s taken straight to the tumours without any effect on normal tissue.”
Cancer scientists are increasingly using targeted delivery to improve results, relying on the many different ‘receptors’ that tumours have for different biological substances.
In this instance, the scientists used the fact that tumours have receptors for transferrin, a plasma protein which transports iron through the blood.
The results have been published in the journal Nanomedicine.
The “ultimate objective” was a clinical trial in humans – but Dr Dufès said that was some way off.
Vegetables that prevent may ultimately cure some cancers
COLLEGE STATION – Broccoli, cabbage, turnips and mustard greens. A dose a day keeps most cancers away.
But for those who develop cancer, the same vegetables may ultimately produce the cure. Research at the Texas Agricultural Experiment Station has led to a patent for a new use for derivatives of DIM, or diindolylmethane, a natural compound derived from certain vegetables, to treat cancer.
“We took advantage of a natural chemical, that research has shown will prevent cancer, and developed several more analogs,” said Dr. Steve Safe, an Experiment Station chemist who has been studying cancer for about 10 years.
Safe’s patent has been picked up by Plantacor, a new biotech company headquartered in College Station, and is expected to enter clinical trials soon in collaboration with M.D. Anderson in Houston.
DIM already is commercially available as a natural supplement for cancer prevention and for treating estrogen-related health issues.
“DIM is a potent substance,” Safe said. “But we made it even more potent against various tumors.”
The first development in this research using chemically altered DIM from broccoli came when the growth of breast cancer cells was inhibited in laboratory studies. Subsequent research showed these compounds also inhibited growth of pancreatic, colon, bladder and ovarian cancer cells in culture, Safe said. Limited trials on lab mice and rats have produced the similar results, he noted.
Safe said the research began by considering compounds that protect a person from developing cancer. Journal articles of other researchers are stacked on Safe’s expansive desk, extolling the scientific evidence that cruciferous vegetables prevent cancer.
His team wondered whether the similar compounds could be developed for treatment of cancer. They looked at the mechanism – how the compounds block cancer cell growth – and found that they target PPAR gamma, a protein that is highly active in fat cells. However, this same PPAR gamma is over-expressed in many tumors and tumor cells and is a potential target for new drugs, he said.
Safe’s lab chemically modified “natural” DIM to give a series of compounds that target the PPAR gamma and stop the growth of cancer.
“One of the best parts is that this treatment appears to have minimal or no side effects, in the mice trials; it just stops tumor growth,” he said. “The hope now is that the patented chemicals can be developed into useful drugs for clinical trials and then be used for cancer treatment.
“It looks promising in cancer cells and animals at this time. We need future studies in humans to see if it is beneficial with people as well,” he added.
(PHILADELPHIA) An herb used in traditional medicine by many Middle Eastern countries may help in the fight against pancreatic cancer, one of the most difficult cancers to treat. Researchers at the Kimmel Cancer at Jefferson in Philadelphia have found that thymoquinone, an extract of nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.
While the studies are in the early stages, the findings suggest that thymoquinone could eventually have some use as a preventative strategy in patients who have gone through surgery and chemotherapy or in individuals who are at a high risk of developing cancer.
According to Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University, nigella sativa helps treat a broad array of diseases, including some immune and inflammatory disorders. Previous studies also have shown anticancer activity in prostate and colon cancers, as well as antioxidant and anti-inflammatory effects.
Using a human pancreatic cancer cell line, she and her team found that adding thymoquinone killed approximately 80 percent of the cancer cells. They demonstrated that thymoquinone triggered programmed cell death in the cells, and that a number of important genes, including p53, Bax, bcl-2 and p21, were affected. The researchers found that expression of p53, a tumor suppressor gene, and Bax, a gene that promotes programmed cell death, was increased, while bcl-2, which blocks such cell death, was decreased. The p21 gene, which is involved in the regulation of different phases of the cell cycle, was substantially increased. She presents her findings May 18 at the Digestive Disease Week in San Diego.
Dr. Arafat and her co-workers also found that thymoquinone caused “epigenetic” changes in pancreatic cancer cells, modifying the cells’ DNA. She explains that these changes involve adding acetyl groups to the DNA structure, specifically to blocks of proteins called histones. This “acetylation” process can be important for genes to be read and translated into proteins. In this case, it could involve the genes that are key to initiating programmed cell death.
“We looked at the status of the histones and found surprisingly that thymoquinone increased the acetylation process,” Dr. Arafat says. “We never anticipated that.”
At the same time, adding thymoquinone to pancreatic cancer cells reduced the production and activity of enzymes called histone deacetylases (HDACs), which remove the acetyl groups from the histone proteins, halting the gene transcription process. Dr. Arafat notes that HDAC inhibitors are a “hot” new class of drugs that interfere with the function of histone deacetylases, and is being studied as a treatment for cancer and neurodegenerative diseases. Finding that thymoquinone functions as an HDAC inhibitor, she says, “was very remarkable and really exciting.”
Pancreatic cancer, the fourth-leading cause of cancer death in this country, takes some 34,000 lives a year. The disease frequently is detected after it has spread and only 4 percent of individuals with pancreatic cancer live for five years after diagnosis
Researchers discover new mechanism behind resistance to cancer treatment
Finding could lead to development of better therapies
SEATTLE – Developing resistance to chemotherapy is a nearly universal, ultimately lethal consequence for cancer patients with solid tumors– such as those of the breast, prostate, lung and colon – that have metastasized, or spread, throughout the body. A team of scientists led by Fred Hutchinson Cancer Research Center has discovered a key factor that drives this drug resistance – information that ultimately may be used to improve the effectiveness of therapy and buy precious time for patients with advanced cancer. They describe their findings online Aug. 5 in advance of print publication in Nature Medicine.
“Cancer cells inside the body live in a very complex environment or neighborhood. Where the tumor cell resides and who its neighbors are influence its response and resistance to therapy,” said senior author Peter S. Nelson, M.D., a member of the Hutchinson Center’s Human Biology Division.
Nelson and colleagues found that a type of normal, noncancerous cell that lives in cancer’s neighborhood – the fibroblast – when exposed to chemotherapy sustains DNA damage that drives the production of a broad spectrum of growth factors that stimulate cancer growth. Under normal circumstances, fibroblasts help maintain the structural integrity of connective tissue, and they play a critical role in wound healing and collagen production.
Specifically, the researchers found that DNA-damaging cancer treatment coaxes fibroblasts to crank out a protein called WNT16B within the tumor neighborhood, or microenvironment, and that high levels of this protein enable cancer cells to grow, invade surrounding tissue and resist chemotherapy.
The researchers observed up to 30-fold increases in WNT production– a finding that was “completely unexpected,”Nelson said. The WNT family of genes and proteins plays an important role in normal development and also in the development of some cancers but, until now, was not known to play a significant role in treatment resistance.
This discovery suggests that finding a way to block this treatment response in the tumor microenvironment may improve the effectiveness of therapy.
“Cancer therapies are increasingly evolving to be very specific, targeting key molecular engines that drive the cancer rather than more generic vulnerabilities, such as damaging DNA. Our findings indicate that the tumor microenvironment also can influence the success or failure of these more precise therapies.” In other words, the same cancer cell, when exposed to different “neighborhoods,” may have very different responses to treatment.
The major clinical reason that chemotherapy ultimately fails in the face of advanced cancer, Nelson said, is because the doses necessary to thoroughly wipe out the cancer would also be lethal to the patient. “In the laboratory we can ‘cure’ most any cancer simply by giving very high doses of toxic therapies to cancer cells in a petri dish. However, in people, these high doses would not only kill the cancer cells but also normal cells and the host.” Therefore, treatments for common solid tumors are given in smaller doses and in cycles, or intervals, to allow the normal cells to recover. This approach may not eradicate all of the tumor cells, and those that survive can evolve to become resistant to subsequent rounds of anti-cancer therapy.
For the study the team of researchers – which also involved investigators at the University of Washington, Oregon Health and Science University, the Buck Institute for Research on Aging, the Lawrence Berkeley National Laboratory – examined cancer cells from prostate, breast and ovarian cancer patients who had been treated with chemotherapy.
“This study is an example of collaborative, translational research that capitalizes on years of federally funded investments into the development of tissue banks and clinical trials in which we were able to track long-term patient outcomes. Investing in this type of infrastructure is critical but may take many years to see payoff,” said Nelson, who serves as principal investigator of the Pacific Northwest Prostate Cancer SPORE, a federally funded, multi-institution research consortium led by the Hutchinson Center.
Cancer-busting chemotherapy can cause damage to healthy cells which triggers them to secrete a protein that sustains tumour growth and resistance to further treatment, a study said Sunday.
Researchers in the United States made the “completely unexpected” finding while seeking to explain why cancer cells are so resilient inside the human body when they are easy to kill in the lab.
They tested the effects of a type of chemotherapy on tissue collected from men with prostate cancer, and found “evidence of DNA damage” in healthy cells after treatment, the scientists wrote in Nature Medicine.
Chemotherapy works by inhibiting reproduction of fast-dividing cells such as those found in tumours.
The scientists found that healthy cells damaged by chemotherapy secreted more of a protein called WNT16B which boosts cancer cell survival.
“The increase in WNT16B was completely unexpected,” study co-author Peter Nelson of the Fred Hutchinson Cancer Research Center in Seattle told AFP.
The protein was taken up by tumour cells neighbouring the damaged cells.
“WNT16B, when secreted, would interact with nearby tumour cells and cause them to grow, invade, and importantly, resist subsequent therapy,” said Nelson.
In cancer treatment, tumours often respond well initially, followed by rapid regrowth and then resistance to further chemotherapy.
Rates of tumour cell reproduction have been shown to accelerate between treatments.
“Our results indicate that damage responses in benign cells… may directly contribute to enhanced tumour growth kinetics,” wrote the team.
The researchers said they confirmed their findings with breast and ovarian cancer tumours.
The result paves the way for research into new, improved treatment, said Nelson.
“For example, an antibody to WNT16B, given with chemotherapy, may improve responses (kill more tumour cells),” he said in an email exchange.
“Alternatively, it may be possible to use smaller, less toxic doses of therapy.”