Honeybee Venom Induced 100% Cancer Cell Death in Lab studies

A specific concentration of honeybee venom can induce 100% cancer cell death, while having minimal effects on normal cells.

“We found that melittin can completely destroy cancer cell membranes within 60 minutes.”

#melittin #honeybeevenom #cancer

Ciara Duffy, Anabel Sorolla, Edina Wang, Emily Golden, Eleanor Woodward, Kathleen Davern, Diwei Ho, Elizabeth Johnstone, Kevin Pfleger, Andrew Redfern, K. Swaminathan Iyer, Boris Baer, Pilar Blancafort. Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer. npj Precision Oncology, 2020; 4 (1) DOI: 10.1038/s41698-020-00129-0

Omega-3 fatty acids more effective at inhibiting growth of triple-negative breast cancer

Contact: Diana Quattrone diana.quattrone@fccc.edu 215-728-7784 Fox Chase Cancer Center

 

 

WASHINGTON, DC (April 9, 2013)—Researchers from Fox Chase Cancer Center have found that omega-3 fatty acids and their metabolite products slow or stop the proliferation, or growth in the number of cells, of triple-negative breast cancer cells more effectively than cells from luminal types of the disease. The omega-3s worked against all types of cancerous cells, but the effect was observed to be stronger in triple-negative cell lines, reducing proliferation by as much as 90 percent. The findings will be presented at the AACR Annual Meeting 2013 on Tuesday, April 9.

Omega-3 fatty acids are found in oily fish like sardines and salmon, and also in oils derived from plants like hemp and flax. Previous studies suggest these compounds can negatively affect critical mechanisms in cancer cells, namely those responsible for proliferation and for apoptosis, or programmed cell death. Lead author on the study Thomas J. Pogash, a scientific technician in the Fox Chase Cancer Center lab of Jose Russo, MD, says the new work underscores the important role common compounds found in food may play in keeping cancer at bay.

“Diet can play a critical role in breast cancer prevention,” says Pogash. “When you compare a western diet to a mediterranean diet, which has more omega-3s, you see less cancer in the mediterranean diet. They eat much more fish.”

Breast cancer is a heterogeneous group of cancers comprising diseases that differ on the molecular level. Patients with different types of breast cancer respond differently to treatments. Four distinct categories of the disease are generally recognized. Two of those, luminal A and luminal B, grow in the luminal cells that line milk ducts in the breast and have receptors for estrogen and progesterone (prognosis is generally better for patients with luminal A than with luminal B). A third category includes tumors that test positive for the HER2 receptor.

Tumors in the fourth category, triple-negative, lack receptors for progesterone, estrogen, and a protein called HER2/neu. As a result, this type of disease is insensitive to treatments like trastuzumab, which disrupts the HER2 receptor, and tamoxifen, which targets the estrogen receptor.

Russo notes that no targeted therapies are currently available for patients diagnosed with triple-negative breast cancer. Combination chemotherapies are the standard of care for early-stage disease.

“This type of cancer, which is found more frequently in Latina and African-American women, is highly aggressive and has a low survival rate,” says Russo. “There is not any specific treatment for it.”

When a cancer cell digests omega-3s, the fatty acid is broken down into smaller molecules called metabolites. Russo, Pogash, and their colleagues tested the effect of large omega-3 parent molecules, as well as their smaller metabolic derivatives, on three luminal cell lines and seven lines that included basal-type triple-negative cells.

Omega-3 and its metabolites were observed to inhibit proliferation in all cell lines, but the effect was dramatically more pronounced in the triple-negative cell lines. In addition, the metabolites of omega-3 reduced the motility, or ability to move, by 20-60 percent in the triple-negative basal cell lines.

This study is part of a consortium between Fox Chase Cancer Center and Pennsylvania State University under a five-year grant awarded by the Komen Foundation. Russo is the principal investigator of the project at Fox Chase. Andrea Manni, MD, leader of the Pennsylvania State University team, has extended this work to animal models, studying the anticancer effects of omega-3s and its metabolites on mouse models of triple-negative breast cancer.

Russo and his colleagues are working on two related projects, one on the role of epigenetic events in the mechanism of cell transformation and another on the potential action of peptides of the hormone human chorionic gonadotropin (hCG) on breast cancer prevention.

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In addition to Russo, Manni, and Pogash, investigators on this project included Ricardo López de Cicco, Benjamin Pressly, and Irma H. Russo at Fox Chase Cancer Center; and Julie A. Himmelberger at DeSales University; and Shantu Amin, Krishne Gowda, and Karam El-Bayoumy at Pennsylvania State University.

Fox Chase Cancer Center, part of Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase also was among the first institutions to receive the National Cancer Institute’s prestigious comprehensive cancer center designation in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are routinely recognized in national rankings, and the Center’s nursing program has achieved Magnet status for excellence three consecutive times. Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research and oversees programs in cancer prevention, detection, survivorship, and community outreach. For more information, call 1-888-FOX-CHASE (1-888-369-2427) or visit http://www.foxchase.org.

Vitamin D Holds Promise in Battling a Deadly Breast Cancer, SLU Researchers Say

January 22, 2013

Carrie Bebermeyer
314.977.8015
Fight Against Triple-Negative Breast Cancer Takes Three Steps Forward
ST. LOUIS — In research published in the Jan. 21 issue of The Journal of Cell Biology, a team led by Susana Gonzalo, Ph.D., assistant professor of biochemistry and molecular biology at Saint Louis University, has discovered a molecular pathway that contributes to triple-negative breast cancer, an often deadly and treatment resistant form of cancer that tends to strike younger women. In addition, Gonzalo and her team identified vitamin D and some protease inhibitors as possible new therapies and discovered a set of three biomarkers that can help to identify patients who could benefit from the treatment.

Susana Gonzalo, Ph.D. with members of her lab team. From left to right, Stanley Kanai, Ignacio Gonzalez-Suarez, David Grotsky, Sree Yaddanapudi, Susana Gonzalo, Abena Redwood and Martin Neumann. This photo appeared in The Journal of Cell Biology.

In the recent breakthrough, which was funded in part by a $500,000 Department of Defense grant, Gonzalo’s lab identified one pathway that is activated in breast cancers with the poorest prognosis, such as those classified as triple-negative. These cancers often strike younger women and are harder to treat than any other type of breast cancer. Women who are born with BRCA1 gene mutations are at increased risk for developing breast and ovarian cancers within their lifetime, and the tumors that arise are frequently the triple-negative type. Although chemotherapy is the most effective treatment for triple-negative breast cancer, it has profound secondary effects. Understanding the biology of triple-negative breast cancers will help to develop less toxic therapeutic strategies.

Experiments performed in Gonzalo’s laboratory, in collaboration with the laboratories of Xavier Matias-Guiu and Adriana Duso (IRBLleida, Spain), showed that activation of this novel pathway not only allows tumor cells to grow unchecked, but also explains the reduced sensitivity of these types of tumors to current therapeutic strategies. Importantly, vitamin D plays a role in turning off this pathway, providing a safe and cost-effective strategy to fight these types of tumors.

THE SCIENCE

For molecular biologists like Gonzalo who look for answers below the cellular level to discover why some people develop cancer, the search often involves tracing a chain of events to try to understand cause and effect of the behavior between several genes and the proteins which they express. In order to understand these complex pathways, researchers often turn levels of proteins on or off by expressing one gene or suppressing another. Part of a researcher’s challenge is determining what the function of each component of a pathway is.

The cell employs a complex mechanism to protect genetic information and ensure that damaged DNA is not passed on to daughter cells. Cells have built in checkpoints and fail safes to ensure the accuracy of their DNA code and are able to slow or stop their own proliferation if the information is compromised. Loss of these checkpoints and the accumulation of damaged DNA often leads to cancer.

The Pathway BRCA1 is a well-established tumor suppressor gene. Women who carry mutations in this gene have a high risk of developing breast and ovarian cancer. Tumors that arise often lack expression of three receptors: estrogen, progesterone and HER2 (thus, “triple-negative”), and do not respond to hormone therapy.

BRCA1 is important because it is involved in repairing DNA double-strand breaks, a kind of DNA damage that is especially dangerous for the integrity of our genome. BRCA1 also is involved in cell-cycle checkpoints after damage, which are control mechanisms during cell proliferation that make sure the DNA information has been accurately replicated and transferred to the daughter cells. Thus, BRCA1 is considered a safeguard of the genome.

Loss of BRCA1 is bad news for the information contained in a cell’s genetic blueprint. It results in genomic instability characterized by unrepaired DNA breaks and chromosomal aberrations that compromise cell viability. How BRCA1-mutated cells are able to form tumors has been a long-standing question. Investigators recently showed that loss of another DNA repair factor, 53BP1, allows proliferation and survival of BRCA1-deficient cells. In addition, decreased levels of 53BP1 were observed in triple-negative breast cancers, and correlated with resistance to drugs at the forefront of cancer treatment, such as PARP inhibitors.

Gonzalo’s team has found a pathway responsible for the loss of 53BP1 in breast cancers with poor prognosis, specifically BRCA1 mutated and triple-negative. It turns out that loss of BRCA1 increases the expression of a protease, known as cathepsin L (CTSL), which causes the degradation of 53BP1. Cells that have lost both BRCA1 and 53BP1 have the ability to repair DNA, maintain the integrity of the genome, and proliferate. Thus, the protease helps cells with faulty BRCA1 to survive.

The Fix If lowering the levels of 53BP1 allows BRCA1 deficient cells to thrive and do their worst, increasing the levels of the protein offers a promising strategy for treatment of breast tumors.

So, how to do this? In previous research, Gonzalo’s team showed that vitamin D inhibits CTSL-mediated degradation of 53BP1 in non-tumor cells, as efficiently as specific CTSL inhibitors. This time, they found that treatment of BRCA1-deficient tumor cells with vitamin D restores high levels of 53BP1, which results in increased genomic instability and reduced proliferation. Importantly, their evidence suggests that vitamin D treatment might restore the sensitivity to PARP inhibitors in patients who become resistant. Thus, a combination of vitamin D and PARP inhibitors could represent a novel therapeutic strategy for breast cancers with poor prognosis.

So, with this chain of events, Gonzalo and colleagues demonstrated a pathway by which triple-negative breast cancers proliferate: BRCA1-deficient cells activate CTSL which minimizes levels of 53BP1 to overcome genomic instability and growth arrest.

The Patients In a final exceptionally useful discovery, Gonzalo and collaborators found that high levels of nuclear CTSL and low levels of 53BP1 and nuclear vitamin D receptor (VDR) are a clear marker that identifies certain triple-negative breast cancer patients, biomarkers that offer the potential to customize future breast cancer therapies. In particular, this triple-biomarker signature will allow the identification of patients in whom the pathway is on and who might benefit the most from vitamin D treatment.

BOTTOM LINE:

  • Researchers have discovered a way in which one of the deadliest and most difficult to treat breast cancers allows tumor cells to grow unchecked and how these tumors resist treatment. Specifically, they found that BRCA1-deficient cells activate CTSL which leads to lower levels of the protein 53BP1 which, in turn, allows cancer cells to grow unchecked.
  • In addition, they discovered the potential for a new therapy involving vitamin D, and identified biomarkers that can help identify which patients could benefit from this therapy.
  • In the future, women with triple-negative breast cancer may benefit from a treatment that includes vitamin D.  As with all laboratory research, vitamin D therapy will have to be studied in a clinical trial before doctors know how safe or effective it will be.
  • Researchers’ next steps will be to study molecular mechanisms behind the activation of the degradation of 53BP1 by CTSL. In addition, preclinical studies with vitamin D and cathepsin inhibitors as single agents or in combination with different drugs are underway in mouse models of breast cancers.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.