Cancer cells are often primed for suicide, but many of them hesitate to pull the trigger. They suppress apoptosis, the suicidal urge, by overexpressing antiapoptotic proteins, which counter proapoptotic proteins and prevent BAX, the “executioner molecule,” from being activated. Cancer cells, however, may be encouraged to follow through on suicidal urges by a newly developed molecule. Even better, this molecule does not seem to speak to healthy cells.
The new molecule, say its developers, may be the first compound that directly induces cancer cells to commit suicide while sparing healthy cells. The molecule is called BTSA1, and it reflects an ambitious screening effort at the Albert Einstein College of Medicine. A team of scientists at Albert Einstein followed up on BAX structural studies by looking for small molecules capable of activating BAX strongly enough to overcome cancer cells’ resistance to apoptosis.
The team, led by Evripidis Gavathiotis, Ph.D., associate professor of biochemistry and of medicine, initially used computers to screen more than one million compounds to reveal those with BAX-binding potential. The most promising 500 compounds – many of them newly synthesized by Dr. Gavathiotis’ team – were then evaluated in the laboratory.
The results of this work appeared October 9 in the journal Cancer Cell, in an article entitled “Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia.” Although this study focused on acute myeloid leukemia (AML) cells, it describes an approach that may also have potential for attacking other types of cancers.
“We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis,” wrote the article’s authors. “BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells.”
Moreover, BTSA1 potently suppressed human AML xenografts and increased host survival without toxicity. Overall, the study’s findings, the authors concluded, provides proof-of-concept for direct BAX activation as a treatment strategy in AML.
“We’re hopeful that the targeted compounds we’re developing will prove more effective than current anticancer therapies by directly causing cancer cells to self-destruct,” said 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.”
AML accounts for nearly one-third of all new leukemia cases and kills more than 10,000 Americans each year. The survival rate for patients has remained at about 30% for several decades, so better treatments are urgently needed.
The newly discovered compound combats cancer by triggering apoptosis—an important process that rids the body of unwanted or malfunctioning cells. Apoptosis trims excess tissue during embryonic development, for example, and some chemotherapy drugs indirectly induce apoptosis by damaging DNA in cancer cells.
Apoptosis occurs when BAX is activated by proapoptotic proteins in the cell. Once activated, BAX molecules home in on and punch lethal holes in mitochondria, the parts of cells that produce energy. But all too often, cancer cells manage to prevent BAX from killing them. They ensure their survival by producing copious amounts of “antiapoptotic” proteins that suppress BAX and the proteins that activate it.
“Our novel compound revives suppressed BAX molecules in cancer cells by binding with high affinity to BAX’s activation site,” explained Dr. Gavathiotis. “BAX can then swing into action, killing cancer cells while leaving healthy cells unscathed.”
“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,” commented lead author Denis Reyna, M.S., a doctoral student in Dr. Gavathiotis’ lab. The researchers next tested BTSA1 in blood samples from patients with high-risk AML. Strikingly, BTSA1 induced apoptosis in the patients’ AML cells but did not affect patients’ healthy blood-forming stem cells.
Finally, the researchers generated animal models of AML by grafting human AML cells into mice. BTSA1 was given to half the AML mice while the other half served as controls. On average, the BTSA1-treated mice survived significantly longer (55 days) than the control mice (40 days), with 43% of BTSA1-treated AML mice alive after 60 days and showing no signs of AML.
Importantly, the mice treated with BTSA1 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,” suggested Dr. Gavathiotis. He noted that his study found that AML cells from patients contained significantly higher BAX levels compared with normal blood cells from healthy people. “With more BAX available in AML cells,” he continued, “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.”
Plans call for Dr. Gavathiotis and his team to see whether BTSA1 will show similar effectiveness when tested on animal models of other types of cancer.