The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells

Abstract

Disease recurrence is the major problem in the treatment of acute myeloid leukemia (AML). Relapse is driven by leukemia stem cells, a chemoresistant subpopulation capable of re-establishing disease. Patients with p53 mutant AML are at an extremely high risk of relapse. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of AML stem cells. Here we studied the effects of a novel small molecule inhibitor of BMI-1, PTC596, in AML cells. Treatment with PTC596 reduced MCL-1 expression and triggered several molecular events consistent with induction of mitochondrial apoptosis: loss of mitochondrial membrane potential, BAX conformational change, caspase-3 cleavage and phosphatidylserine externalization. PTC596 induced apoptosis in a p53-independent manner. PTC596 induced apoptosis along with the reduction of MCL-1 and phosphorylated AKT in patient-derived CD34+CD38low/− stem/progenitor cells. Mouse xenograft models demonstrated in vivo anti-leukemia activity of PTC596, which inhibited leukemia cell growth in vivo while sparing normal hematopoietic cells. Our results indicate that PTC596 deserves further evaluation in clinical trials for refractory or relapsed AML patients, especially for those with unfavorable complex karyotype or therapy-related AML that are frequently associated with p53 mutations.

Acute Myeloid Leukemia Driven by the CALM-AF10 Fusion Gene is Dependent on BMI1

“…have been used to demonstrate that a broad panel of human AML cell lines are sensitive to small-molecule BMI1 inhibition (Mourgues et al, 2015;Nishida et al, 2015Nishida et al, , 2017 although none of these studies focused specifically on CALM-AF10-rearranged AML. In CALM-AF10, the clinical rationale for BMI1 targeting may be clearer, given that BMI1 is strongly upregulated in CALM-AF10 rearranged AML.…”

Targeting BMI1 and MCL1 for Lung Adenocarcinoma Treatment

“…The first BMI1 inhibitor PTC-209 was reported in 2014 (12), which showed promising anti-cancer effect in pre-clinical model of several types of tumors (12-14). Unfortunately, PTC-209 has not entered clinical trials because of poor pharmacokinetic properties (15). Another BMI1 inhibitor, PTC-596, which demonstrated in vivo anti-leukemia activity and showed a favorable safety profile (15, 16), has recently entered Phase 1 clinical trials.…”

“…Unfortunately, PTC-209 has not entered clinical trials because of poor pharmacokinetic properties (15). Another BMI1 inhibitor, PTC-596, which demonstrated in vivo anti-leukemia activity and showed a favorable safety profile (15, 16), has recently entered Phase 1 clinical trials.…”

Resveratrol Sensitizes Lung Cancer Cell to TRAIL by p53 Independent and Suppression of Akt/NF-κB Signaling

“…Additionally, the p53 transcription factor can induce cell cycle arrest, DNA damage, cellular senescence, and apoptosis in different cancer cell types [22,23]. p53 independent apoptosis cascade formation also now considerable issue [24,25]. NF-κB (p65), a pro-inflammatory transcription factor that is activated by numerous inflammatory agents, tumor promoters, carcinogens, and the tumor microenvironment could also promote tumorigenesis.…”