Scientists have discovered the first compound that directly drives cancer cells to commit suicide while sparing healthy cells, paving the way for faster and more efficient treatments with fewer side effects. The new treatment approach developed by researchers at Albert Einstein College of Medicine in the US was directed against acute myeloid leukaemia (AML) cells.
The compound called BTSA1 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, researchers said. Apoptosis occurs when BAX – the “executioner protein” in cells – is activated by “pro-apoptotic” proteins in the cell.
Once activated, BAX molecules home in on and punch lethal holes in mitochondria, the parts of cells that produce energy, they said. However, often cancer cells manage to prevent BAX from killing them. They ensure their survival by producing copious amounts of “anti-apoptotic” proteins that suppress BAX and the proteins that activate it, researchers said. “Our novel compound revives suppressed BAX molecules in cancer cells by binding with high affinity to BAX’s activation site,” said Evripidis Gavathiotis, associate professor at Albert Einstein College of Medicine.
BAX can then swing into action, killing cancer cells while leaving healthy cells unscathed, researchers said. “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 Denis Reyna, a doctoral student in 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.
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 per cent of BTSA1-treated AML mice alive after 60 days and showing no signs of AML. 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,” said Gavathiotis. “We are hopeful that the targeted compounds we are developing will prove more effective than current anti-cancer therapies by directly causing cancer cells to self-destruct,” Gavathiotis said. “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,” Gavathiotis added.