Researchers reduce breast cancer metastasis in animal models by
modifying tumor electrical properties
Amiodarone, an ion channel blocker approved for other diseases,
significantly inhibits tumor cell invasion

Date:
January 11, 2022
Source:
Tufts University
Summary:
Researchers have found that manipulating voltage patterns of
tumor cells -- using ion channel blockers already FDA-approved as
treatments for other diseases -- can in fact significantly reduce
metastasis in animal models of breast cancer.



FULL STORY ==========================================================================
In normal cells, electrical voltage patterns provide a blueprint for
orderly growth. But with cancer, the opposite happens. Marked by a
breakdown in the normal electrical patterns generated by the cells,
they lose their specialized functions, start expanding into a tumor
and spreading into and disrupting the function of other tissues --
metastasis. As of yet, there are no clinically available treatments that specifically target the process of metastasis, which remains the leading
cause of death in cancer patients.


==========================================================================
Now researchers at Tufts University have found that manipulating voltage patterns in tumor cells using ion channel blockers already FDA-approved as treatments for other diseases can in fact significantly reduce tumor cell invasion in a dish and metastasis in an animal model of breast cancer.

The discovery, published in eBioMedicine, showed that drugs already
approved for other conditions can slow or stop metastasis could lead to
an expedited path to approval for the treatment of cancer.

"This is very much an unexplored, but highly opportunistic strategy
for the treatment of cancer," said Madeleine Oudin, Tiampo Family
Assistant Professor of biomedical engineering at 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 ready-to-use drugs that could be repurposed for cancer therapy."
To test their therapeutic strategy, the Tufts research team focused
on triple- negative breast cancer (TNBC), a subtype of the disease
which accounts for approximately 15% of all breast cancer cases. The
likelihood of metastasis for TNBC is greater than all other subtypes
of breast cancer, and because TNBC is associated with a poor five-year prognosis, scientists are focusing efforts on counteracting 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 mouse lungs
by about 50%.



========================================================================== Cells in the body create a natural voltage across their membranes,
caused by ion channels that actively push or passively allow positive
and negative ions into and out of the cell. Mike Levin, Vannevar Bush
Professor in the Department Biology, a collaborator on this study, has
been working on dissecting the role of electrical properties in cellular behaviors for many years in model organisms. When Oudin joined Tufts,
they received funding through the Tufts Collaborates program, which
helps support collaborations between faculty in different schools to
tackle new exciting areas of research.

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 ion channels tend to
dominate in generating the voltage across the cell membrane. When the
Tufts researchers genetically over- expressed the potassium ion channels
in tumor cells, the inside of the cells became more negatively charged,
and the imbalance in voltage led to increased tumor growth and metastasis,
both in plated cells and animal models.

The researchers' therapeutic strategy took the opposite approach --
blocking the potassium ion channels led to a restoration of more normal voltages for the cells, decreased tumor cell invasion and significantly reducing metastasis.

Four FDA-approved potassium ion channel blockers were screened, and all
had similar effectiveness in killing tumors cells. One drug, amiodarone,
had the largest effect on 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 treating heart rhythm disorders, cut back on the tumors' ability to spread as cells broke off
and move to other parts of the body.

By looking at the genes that were triggered by the voltage shift,
they found a number of molecular pathways involved in the movement of
cells. The effects of the ion channel blocking drug were consistent with limiting the cells movement, so they don't wander off and grow new tumors.

"Our results with amiodarone were very exciting because they suggest that
by targeting the bioelectric properties of tumor cells we were able to specifically target the cells that leave the primary tumor, i.e., the
harder to kill metastatic cells. Our findings suggest that a drug like amiodarone that can change the bioelectric properties of cancer cells
might one day be combined with an existing chemotherapeutic drug that
inhibits tumor cell growth for a more effective cancer treatment." said Samantha Payne, a biomedical researcher in Oudin's lab and first author
of the study.

The Tufts team will continue to explore the effects of the ion channel
blockers on cancer in animal models, in combination with existing standard
of care treatments like chemotherapy. Since amiodarone and similar drugs
are already approved for use in humans, phase I clinical trials in small
groups of cancer patients could commence in the near future.

========================================================================== Story Source: Materials provided by Tufts_University. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220111100030.htm

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