OCT 10, 2017 3:44 PM PDT

New Drug Revives 'Executioner Protein' to Kill Cancer Cells

WRITTEN BY: Xuan Pham

Image credit: Pixabay.com

After nearly a decade of searching, scientists from the Albert Einstein College of Medicine have found a molecule that triggers death in cancer cells without harming healthy cells. The discovery was successfully tested against acute myeloid leukemia (AML) cells, and the team is optimistic it’ll also work against other cancer types as well.

Cells have a built-in mechanism for self-destruction, also known as apoptosis. This mechanism prevents cells that are too old or too abnormal to continue dividing and passing on unwanted mutations to future generations of cells.

One key protein in this apoptosis process is BAX, also dubbed the “executioner protein.” When activated, this protein causes the cell’s mitochondria to become leaky, which eventually leads to cell death.

This system works brilliantly for healthy cells. Cancer cells, on the other hand, have found a way to suppress BAX. This affords cancer cells indefinite life cycles and the ability to proliferate and make more cancer cells.

Led by Evripidis Gavanthiotis, the research team at Albert Einstein College of Medicine searched for a molecule that can free BAX in cancer cells, which would force cancer cells to self-destruct.

"Our novel compound revives suppressed BAX molecules in cancer cells by binding with high affinity to BAX's activation site," says Dr. Gavathiotis, associate professor of biochemistry and of medicine, and the study’s senior author. "BAX can then swing into action, killing cancer cells while leaving healthy cells unscathed."

After screening through 500 new compounds, the team landed on one that had the best BAX-binding potential, BTSA1.

"A compound dubbed BTSA1 (short for BAX Trigger Site Activator 1) proved to be the most potent BAX activator, causing rapid and extensive apoptosis when added to several different human AML cell lines," says Denis Reyna, a doctoral student in Dr. Gavathiotis' lab, and the study’s lead author.

In AML cells, BTSA1 induced cell death quickly without harming the healthy cells. In a mouse model of AML, animals given BTSA1 survived longer than untreatread mice. Furthermore, 43 percent of treated mice had no evidence of AML after 60 days, offering hope that the effects of BTSA1 may be long-lasting.

That BTSA1 triggered suicide in AML cancer cells and not healthy cells is a great victory. Too often, the treatment is not specific enough to the cancer and will, therefore, also cause collateral damage to the healthy cells. The team thinks the specificity of BTSA1 may be due to the abundance of suppressed BAX proteins found in cancer cells.

"BTSA1 activates BAX and causes apoptosis in AML cells while sparing healthy cells and tissues -- probably because the cancer cells are primed for apoptosis," says Dr. Gavathiotis. "With more BAX available in AML cells, even low BTSA1 doses will trigger enough BAX activation to cause apoptotic death, while sparing healthy cells that contain low levels of BAX or none at all."

The team will soon test the compound in other animal models and other types of cancer.

"We're hopeful that the targeted compounds we're developing will prove more effective than current anti-cancer therapies by directly causing cancer cells to self-destruct," says Dr.Gavathiotis, "Ideally, our compounds would be combined with other treatments to kill cancer cells faster and more efficiently -- and with fewer adverse effects, which are an all-too-common problem with standard chemotherapies."

Additional sources: Albert Einstein College of Medicine 

 

About the Author
I am a human geneticist, passionate about telling stories to make science more engaging and approachable. Find more of my writing at the Hopkins BioMedical Odyssey blog and at TheGeneTwist.com.
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