MADRID, 12 (EUROPA PRESS)
Researchers at Tufts University in Boston (USA) have discovered that manipulating voltage patterns in tumor cells, using ion channel blockers already approved by the US Food and Drug Administration (FDA) as treatments for other diseases, can significantly reduce tumor cell invasion into a plaque and metastasis in an animal model of breast cancer.
The discovery, published in eBioMedicine, has shown that drugs already approved for other conditions can slow or stop metastasis and could lead to an accelerated path to approval for cancer treatment. “This is a very little explored, but highly opportunistic strategy for cancer treatment,” said Madeleine Oudin, Tiampo Family Assistant Professor of Biomedical Engineering in the Tufts University School of Engineering and corresponding author of the study.
“Ion channels, which regulate the bioelectrical properties of cells, are the second most common target for existing pharmaceuticals, so we have a relatively large set of off-the-shelf drugs that could be repurposed for cancer therapy.” added the expert, who hopes to start phase 1 studies in small groups of patients in the near future.
In normal cells, electrical voltage patterns provide a blueprint for orderly growth. But with cancer the opposite happens. Marked by a break in the normal electrical patterns generated by cells, they lose their specialized functions, begin to expand into a tumor, and spread and disrupt the function of other tissues: metastases. To date, there are no clinically available treatments that specifically target the process of metastasis, which remains the leading cause of death in cancer patients.
FOCUSED ON TRIPLE NEGATIVE BREAST CANCER
To test their therapeutic strategy, the Tufts research team focused on triple-negative breast cancer (TNBC), a subtype of the disease that accounts for approximately 15 percent of all breast cancer cases. The likelihood of metastasis from TNBC is greater than that of all other breast cancer subtypes, and because TNBC is associated with a poor five-year prognosis, scientists are focusing their efforts on countering it.
The researchers were able to show that manipulating the voltage properties of breast cancer cells can have a significant effect on their progression to metastasis, reducing the number of metastatic sites in the lungs of mice by about 50 percent. Cells in the body create a natural voltage across their membranes, caused by ion channels that activate or passively allow positive and negative ions to enter and leave the cell.
Mike Levin, Vannevar Bush Professor in the Department of Biology, a collaborator on this study, has been working for many years dissecting the role of electrical properties in cellular behaviors in model organisms. When Oudin joined Tufts, they received funding through the Tufts Collaborates program, which helps support collaborations between faculty from different schools to address new and exciting areas of research.
Although there are a variety of channels that drive the movement of positively charged sodium, calcium, and potassium ions, as well as negatively charged chloride ions, potassium ion channels tend to dominate in generating voltage across the cellular membrane. When the Tufts researchers genetically overexpressed potassium ion channels in tumor cells, the interior of the cells became more negatively charged and the imbalance in voltage led to increased tumor growth and metastasis, both in plated cells and in models. animals.
The researchers’ therapeutic strategy took the opposite approach: blockade of potassium ion channels led to restoration of more normal voltages for cells, decreased tumor cell invasion, and significantly reduced metastasis.
Four FDA-approved potassium ion channel blockers were tested and all had similar efficacy in killing tumor cells. One drug, amiodarone, had the greatest effect in normalizing cell voltages and was selected to see how well it would work in treating breast cancer in mice. The researchers found that the drug, approved for use in treating heart rhythm disorders, reduced the ability of tumors to spread as cells broke apart and moved to other parts of the body.
By looking at the genes that were triggered by the voltage change, they found a number of molecular pathways involved in cell movement. The effects of the ion channel blocking drug were consistent with limiting the movement of cells, so they don’t stray and develop new tumors.
“Our results with amiodarone were very exciting because they suggest that by targeting the bioelectrical properties of tumor cells we were able to specifically target cells that are leaving the primary tumor, that is, the hardest-to-kill metastatic cells. Our findings suggest that a drug like amiodarone that can change the bioelectrical properties of cancer cells could one day be combined with an existing chemotherapy drug that inhibits tumor cell growth for more effective cancer treatment,” said Samantha Payne, a researcher biomedical researcher in Oudin’s lab and first author of the study.
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