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Now, researchers at Tufts University have found that controlling the voltage patterns of tumor cells using an ion channel blocker, a drug already approved by the FDA to treat other diseases, can actually significantly reduce tumor cell invasion in a petri dish and metastasis in animal models of breast cancer
.
The findings, published in the journal eBioMedicine, suggest that drugs already approved for other diseases can slow or stop metastasis, potentially speeding up the approval process for cancer treatments
.
"This is a very unexplored, but very opportunistic cancer treatment strategy," 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 modulate the bioelectric properties of cells, are the second most common target of existing drugs, so we have a relatively large set of off-the-shelf drugs that can be repurposed for cancer treatment
To test their treatment strategy, the Tufts team focused on triple-negative breast cancer (TNBC), a subtype of the disease that accounts for about 15 percent of all breast cancer cases
.
Tertiary breast cancer is more likely to metastasize than all other subtypes, and because of its poor five-year prognosis, scientists are working to combat it
The researchers were able to show that manipulating the voltage properties of breast cancer cells could have a dramatic effect on their metastatic progression, reducing the number of metastatic sites in the lungs of mice by about 50 percent
.
Cells in the body generate a natural voltage across their cell membranes, which is caused by ion channels that either actively push or passively allow positive and negative ions to enter and leave the cell
While 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 channels tend to dominate in generating the voltage across cell membranes
.
When Tufts University researchers overexpressed potassium channels in tumor cells, the interior of the cells became more negatively charged, and the voltage imbalance led to increased tumor growth and metastasis, both in plate cells and in animal models in all
The researchers' treatment strategy took the opposite approach—blocking potassium channels restored the cells to a more normal voltage, reduced tumor cell invasion, and significantly reduced metastasis
.
Four FDA-approved potassium channel blockers were screened, all of which were similarly effective in killing tumor cells
.
One of the drugs, amiodarone, had the greatest effect on normal cell voltage, and the researchers chose amiodarone to see its effect on treating breast cancer in mice
By looking at the genes that were triggered by voltage changes, they discovered a number of molecular pathways involved in cell movement
.
The effect of ion channel-blocking drugs is consistent with restricting cell movement so that they don't dissociate and create new tumors
"Our results with amiodarone are very exciting because they show that by targeting the bioelectric properties of tumor cells, we can specifically target cells that have left the primary tumor, i.
e.
are harder to kill metastatic cells
"Our research shows that drugs such as amiodarone that can alter the biological properties of tumor cells may one day be combined with existing chemotherapy drugs that can inhibit tumor cell growth for more effective cancer treatments
.
" Samantha Payne said, Odin Biomedical Researcher's lab and lead author of the study
The Tufts research team will continue to explore the effects of ion channel blockers on cancer in animal models, in conjunction with existing standard-of-care treatments, such as chemotherapy
.
Since amiodarone and similar drugs are already approved for use in humans, phase I clinical trials in small groups of cancer patients may begin in the near future
Journal Reference :
Samantha L.
Payne, Priyanka Ram, Deepti H.
Srinivasan, Thanh T.
Le, Michael Levin, Madeleine J.
Oudin.
Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer .
eBioMedicine , 2022; 75: 103767 DOI: 10.
1016/j.
ebiom.
2021.
103767 htm (accessed January 11, 2022).
