Treatment Causes Cancer Cells to Self-Destruct – but Spares Healthy Cells

This image depicts the structure of the BAX protein (purple). The activator compound BTSA1 (orange) has bound to the active site of BAX (green), changing the shape of the BAX molecule at several points (shown in yellow, magenta and cyan). BAX, once in its final activated form, can home in on mitochondria and puncture their outer membranes, triggering apoptosis (cell death). Image courtesy Albert Einstein College of Medicine

(CN) – Researchers have created a new treatment that can kill cancer directly without affecting healthy cells – a development that could dramatically improve survival rates of patients suffering from the disease.

The novel approach, which the team describes Monday in the journal Cancer Cell, relies on a newly discovered compound that forces cancer cells to “commit suicide.” The team tested the treatment on acute myeloid leukemia (AML) cells.

AML represents nearly one-third of all new leukemia cases and kills more than 10,000 Americans annually. The survival rate for AML has hovered around 30 percent for several decades.

“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, an associate professor of biochemistry and medicine at the Albert Einstein College of Medicine.

“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.”

The compound fights cancer by triggering apoptosis – a vital process that rids the body of unwanted or malfunctioning cells. Apoptosis removes excess tissue during embryonic development, and some chemotherapy drugs indirectly induce the process by damaging DNA in cancer cells.

Apoptosis begins when BAX, which is the “executioner protein” in cells, is activated by “pro-apoptotic” proteins in a cell. Upon activation, BAX molecules punch lethal holes in mitochondria, which produce energy in cells. In many cases, cancer cells can prevent BAX from killing them by producing significant amounts of “anti-apoptotic” proteins that suppress BAX and the proteins that trigger it.

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

After publishing a 2008 report in Nature that first described the shape and structure of BAX’s activation site, Gavathiotis has been searching for small molecules that can activate BAX strongly enough to overwhelm cancer cells’ resistance to apoptosis. His team used computers to analyze more than 1 million compounds in order to identify those with BAX-binding potential. The 500 most promising candidates – many of which were first synthesized by the team – were then evaluated in Gavathiotis’ lab.

“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, a doctoral student at Albert Einstein.

After discovering the compound, the team then tested BTSA1 in blood samples from patients with high-risk AML. The compound induced apoptosis in the samples without affecting the patients’ healthy, blood-forming stem cells.

Lastly, the researchers created animal models by grafting human AML cells into mice. Half of the AML mice were given BTSA1, while the rest served as controls. On average, BTSA1-treated mice lived significantly longer than control mice – 55 days and 40 days, respectively. Of the BTSA1-treated mice, about 43 percent lived more than 60 days and showed no signs of AML.

The mice treated with BTSA1 also showed no evidence of toxicity.

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

The team notes that the patients’ AML cells contained much higher BAX levels than normal blood cells from healthy people.

“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,” Gavathiotis said.

The team now plans to test the treatment of other types of cancer on animal models.

 

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