Maritoclax induces apoptosis in acute myeloid leukemia cells with elevated Mcl-1 expression

Abstract

Acute myeloid leukemia (AML) is one of the deadliest leukemias for which there is an urgent and unmet need for the development of novel treatment strategies. Multiple drug resistance mechanisms mediate poor drug response and relapse in patients, and a selective Mcl-1 inhibitor has been speculated to be a promising agent in the treatment of AML. Here, we describe that maritoclax, a small molecule Mcl-1 inhibitor, induces Mcl-1 proteasomal degradation without transcriptional downregulation. Maritoclax killed AML cell lines and primary cells with elevated Mcl-1 levels through selective Mcl-1 downregulation, and synergized with ABT-737 to overcome Mcl-1-mediated ABT-737 resistance. Maritoclax was more effective than daunorubicin at inducing leukemic cell death when co-cultured with HS-5 bone marrow stroma cells, while being less toxic than daunorubicin against HS-5 stroma cells, primary mouse bone marrow cells, and hematopoietic progenitor cells. Moreover, maritoclax administration at 20 mg/kg/d intraperitoneally caused significant U937 tumor shrinkage, as well as 36% tumors remission rate in athymic nude mice, without apparent toxicity to healthy tissue or circulating blood cells. In summary, our studies suggest that maritoclax belongs to a novel class of Mcl-1 inhibitors that has the potential to be developed for the treatment of AML.

Keywords: :

• leukemia
• acute myeloid leukemia
• Mcl-1
• Bcl-2
• maritoclax
• ABT-737

Disclosures of Conflict of Interest

The authors declare no conflicts of interest.

Acknowledgments

We thank Su-Fern Tan and Dan Zhang from Dr Thomas Loughran’s lab for graciously providing reagents, cell lines, and antibodies. We thank Dr Timothy K Cooper for the complete histological examination of experimental mice. We also thank Dr Gerard Grosveld for graciously providing the MSCV-Luciferase-IRES-YFP construct. This work was supported by the Lois High Berstler Endowment Fund and the Four Diamonds Fund of the Pennsylvania State University College of Medicine.