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Researchers say they have discovered a compound that can overcome resistance to apoptosis in acute myeloid leukemia (AML).
The compound, BTSA1, works by activating the BCL-2 family protein BAX.
BTSA1 prompted apoptosis in leukemia cells while sparing healthy cells. It also suppressed AML in mice without producing side effects.
Evripidis Gavathiotis, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues described these results in Cancer Cell.
The team knew that apoptosis occurs when BAX is activated by pro-apoptotic proteins. However, cancer cells can avoid apoptosis by producing anti-apoptotic 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,” Dr Gavathiotis said. “BAX can then swing into action, killing cancer cells while leaving healthy cells unscathed.”
Dr Gavathiotis was the lead author of a paper published in Nature in 2008 that first described the structure and shape of BAX’s activation site. He has since looked for small molecules that can activate BAX strongly enough to overcome cancer cells’ resistance to apoptosis.
His team initially screened more than 1 million compounds to reveal those with BAX-binding potential. The most promising 500 compounds were then evaluated in the 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 Denis Reyna, a doctoral student in Dr Gavathiotis’s lab.
The researchers also tested BTSA1 in blood samples from patients with high-risk AML. BTSA1 induced apoptosis in the patients’ AML cells but did not affect healthy hematopoietic stem cells.
Finally, the researchers generated mouse models of AML. BTSA1 was given to half the mice, while the other half served as controls.
On average, the BTSA1-treated mice survived significantly longer than the control mice—55 days and 40 days, respectively (P=0.0009). In fact, 43% of BTSA1-treated mice were still alive after 60 days and showing no signs of AML.
In addition, 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,” Dr Gavathiotis said.
He and his colleagues found that AML cells contained significantly higher BAX levels than normal blood cells from healthy subjects.
“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 said.
He and his team plan to determine if BTSA1 will elicit similar results in other cancer types. 
Researchers say they have discovered a compound that can overcome resistance to apoptosis in acute myeloid leukemia (AML).
The compound, BTSA1, works by activating the BCL-2 family protein BAX.
BTSA1 prompted apoptosis in leukemia cells while sparing healthy cells. It also suppressed AML in mice without producing side effects.
Evripidis Gavathiotis, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues described these results in Cancer Cell.
The team knew that apoptosis occurs when BAX is activated by pro-apoptotic proteins. However, cancer cells can avoid apoptosis by producing anti-apoptotic 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,” Dr Gavathiotis said. “BAX can then swing into action, killing cancer cells while leaving healthy cells unscathed.”
Dr Gavathiotis was the lead author of a paper published in Nature in 2008 that first described the structure and shape of BAX’s activation site. He has since looked for small molecules that can activate BAX strongly enough to overcome cancer cells’ resistance to apoptosis.
His team initially screened more than 1 million compounds to reveal those with BAX-binding potential. The most promising 500 compounds were then evaluated in the 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 Denis Reyna, a doctoral student in Dr Gavathiotis’s lab.
The researchers also tested BTSA1 in blood samples from patients with high-risk AML. BTSA1 induced apoptosis in the patients’ AML cells but did not affect healthy hematopoietic stem cells.
Finally, the researchers generated mouse models of AML. BTSA1 was given to half the mice, while the other half served as controls.
On average, the BTSA1-treated mice survived significantly longer than the control mice—55 days and 40 days, respectively (P=0.0009). In fact, 43% of BTSA1-treated mice were still alive after 60 days and showing no signs of AML.
In addition, 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,” Dr Gavathiotis said.
He and his colleagues found that AML cells contained significantly higher BAX levels than normal blood cells from healthy subjects.
“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 said.
He and his team plan to determine if BTSA1 will elicit similar results in other cancer types.
Researchers say they have discovered a compound that can overcome resistance to apoptosis in acute myeloid leukemia (AML).
The compound, BTSA1, works by activating the BCL-2 family protein BAX.
BTSA1 prompted apoptosis in leukemia cells while sparing healthy cells. It also suppressed AML in mice without producing side effects.
Evripidis Gavathiotis, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues described these results in Cancer Cell.
The team knew that apoptosis occurs when BAX is activated by pro-apoptotic proteins. However, cancer cells can avoid apoptosis by producing anti-apoptotic 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,” Dr Gavathiotis said. “BAX can then swing into action, killing cancer cells while leaving healthy cells unscathed.”
Dr Gavathiotis was the lead author of a paper published in Nature in 2008 that first described the structure and shape of BAX’s activation site. He has since looked for small molecules that can activate BAX strongly enough to overcome cancer cells’ resistance to apoptosis.
His team initially screened more than 1 million compounds to reveal those with BAX-binding potential. The most promising 500 compounds were then evaluated in the 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 Denis Reyna, a doctoral student in Dr Gavathiotis’s lab.
The researchers also tested BTSA1 in blood samples from patients with high-risk AML. BTSA1 induced apoptosis in the patients’ AML cells but did not affect healthy hematopoietic stem cells.
Finally, the researchers generated mouse models of AML. BTSA1 was given to half the mice, while the other half served as controls.
On average, the BTSA1-treated mice survived significantly longer than the control mice—55 days and 40 days, respectively (P=0.0009). In fact, 43% of BTSA1-treated mice were still alive after 60 days and showing no signs of AML.
In addition, 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,” Dr Gavathiotis said.
He and his colleagues found that AML cells contained significantly higher BAX levels than normal blood cells from healthy subjects.
“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 said.
He and his team plan to determine if BTSA1 will elicit similar results in other cancer types.