The Dance of Death

A male scientist with eyeglasses studies cells under a microscope.
By Laura Bailey

If finding the cure for cancer was as simple as a boxing match, the microscopic cancer stem cells wouldn’t stand a chance against heavyweight scientists today. But it’s not that simple, especially when the opponent is a cancer stem cell fighting to survive against anticancer drugs.

What happens when cancer fights back?

Findings from a 2007 research study conducted at the Uniformed Services University of the Health Sciences (USU) indicated some anticancer treatments were found to have the unintended effect of spreading, rather than killing, cancer.

“These cells are trying to find a way to survive the therapy," said Vasyl Vasko, M.D., PhD., a scientist in the Department of Pediatrics in USU’s F. Edward Hebert School of Medicine. "This may help explain why the expression of stem cell markers has been associated with resistance to chemotherapy and radiation treatments and poor outcome for patients with cancers including prostate, breast and lung cancers."

A male scientist with eyeglasses points to a computer screen with several boxes of green and orange cell shapes on them.
Vasyl Vasko, MD, Ph.D., discusses his research and explains the various color-coded cancer cells he’s been studying.  (Image Credit: Sharon Holland)
Vasko’s continued research, following the 2007 report, dealt a massive blow to thyroid cancer when he and a team of scientists discovered what was right under their noses – metformin, a popular anti-diabetes drug already on the market.

Metformin combined with glycolysis inhibitors prevents cancer growth by activating a protein called AMP-inducible protein kinase or AMPK. Glycolysis inhibitors, drugs that prevent the breakdown of sugar, are a key factor in determining metformin anticancer activity.

Here’s why. Cancer cells have to move around to replicate. Moving around requires energy. Energy comes from the breakdown of sugar. If sugar can’t be broken down, then cancer cells can’t move, and if they can’t move, they can’t replicate. Metformin acts like a knockout punch. While the cancer cells are down for the count, metformin is free to invade. Once inside, metformin activates AMPK. The cancer cell, realizing there’s a threat, re-animates and attempts to fight back by replicating itself, but by then, it’s too late. Metformin delivers the final blow, causing a reaction known as oncosis, and what scientists call the “dance of death.”

Cancer cells treated with with a commonly used anti-diabetic medication, Metformin, undergo visible structural changes indicative of cell death.  These structural changes occurred gradually, with time points corresponding to the following stages:  non-reactive stage (24 hours), cell swelling (24-36 hours), cell shrinkage (36-40 hours), detachment from the culture plate (40-48 hours) and finally an out pouching of the cellular membrane (48-72 hours). 

One of the greatest advantages of metformin as a cancer treatment is its low toxicity. Chemotherapy and radiation treatments are highly toxic, Vasko explained. It is this toxicity that causes cancer patients undesirable side effects such as hair loss, vomiting, intense pain, mouth sores, and diarrhea, just to name a few. Metformin, on the other hand, has a low toxicity rate, targets only cancer cells, and is already available – another huge advantage.

“Let’s say that right now I discover a brand new cure for cancer and I want to release it so that cancer patients can start benefiting from the drug. It would take ten years to get that drug approved for a clinical trial because there are so many tests a new drug must undergo and pass before it can be approved for human use,” said Vasko. “Metformin is already approved so we don’t have to wait.”

This leaves only one question. What’s next?

Currently, he is working on identifying gender-specific therapies for thyroid cancer because thyroid cancer has been shown to be more prevalent in women, he said. Vasko hopes that understanding the gender-specific pathways of thyroid cancer will lead to targeted therapies for both men and women.

Advances in cancer treatment at USU surely lie ahead, and the dance of death continues.