Investigational Therapy Induces Cancer Cell Death

Novel drug causes apoptosis in leukemia cells, while leaving healthy blood cells unscathed.

Researchers recently made the groundbreaking discovery of the first compound that causes cancer cells to self-destruct, while leaving healthy cells unaffected. The treatment approach was successful in acute myeloid leukemia (AML) cells, but may also treat other cancers, according to a study published by Cancer Cell.

“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,” said senior author Evripidis Gavathiotis, PhD. “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.”

Despite the prevalence of AML, the survival rate of the condition has remained at 30% for decades, underscoring the need for better treatment approaches, according to the authors.

The experimental compound triggers apoptosis, which is a process that kills damaged or unneeded cells. Certain chemotherapies induce apoptosis by altering cancer cell DNA, according to the authors.

Apoptosis occurs when BAX is activated by certain proteins. After this, BAX puts holes in the mitochondria of the cell. However, cancer cells can avoid death by producing anti-apoptotic proteins that suppress BAX and proteins that activate it, according to the study.

“Our novel compound revives suppressed BAX molecules in cancer cells by binding with high affinity to BAX’s activation site,” Dr Gavathiotis said. “BAX can then swing into action, killing cancer cells while leaving healthy cells unscathed.”

Previously, the authors outlined BAX’s activation site. The team of researchers then searched for small molecules that can strongly activate BAX in order to bypass cancer cell resistance.

The investigators screened more than 1 million compounds for BAX-binding ability and tested the 500 most promising candidates.

“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,” said lead author Denis Reyna, MS.

The authors analyzed BTSA1 in blood samples from human patients with high-risk AML and discovered that it caused apoptosis in AML cells without affecting healthy stem cells, according to the study.

In animal models of AML, mice treated with BTSA1 survived for 55 days, while control mice survived for 40 days, a significant survival difference. The authors also noted that BTSA1-treated mice were alive after 60 days and did not have any signs of cancer, according to the study.

Notably, mice treated with BTSA1 did not cause toxicity in the animals, which is an advantage over current therapies.

“BTSA1 activates BAX and causes apoptosis in AML cells while sparing healthy cells and tissues—probably because the cancer cells are primed for apoptosis,” Dr Gavathiotis said.

The authors also discovered that AML cells from humans had higher levels of BAX compared with blood cells from healthy patients, according to the study.

“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,” Dr Gavathiotis concluded.