Maritoclax induces apoptosis in acute myeloid leukemia cells with elevated Mcl-1 expression.
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.
Department of Pediatrics; Pennsylvania State University College of Medicine; Hershey, PA USA.
Kenichiro
K
Doi
Department of Pharmacology; Pennsylvania State University College of Medicine; Hershey, PA USA.
Qiang
Q
Liu
Department of Pharmacology; Pennsylvania State University College of Medicine; Hershey, PA USA.
Krishne
K
Gowda
Penn State Hershey Cancer Institute; Pennsylvania State University College of Medicine; Hershey, PA USA.
Brian M
BM
Barth
Penn State Hershey Cancer Institute; Pennsylvania State University College of Medicine; Hershey, PA USA.
David
D
Claxton
Department of Pharmacology; Pennsylvania State University College of Medicine; Hershey, PA USA.
Shantu
S
Amin
Penn State Hershey Cancer Institute; Pennsylvania State University College of Medicine; Hershey, PA USA.
Thomas P
TP
Loughran
Department of Pediatrics; Pennsylvania State University College of Medicine; Hershey, PA USA; Department of Pharmacology; Pennsylvania State University College of Medicine; Hershey, PA USA; Penn State Hershey Cancer Institute; Pennsylvania State University College of Medicine; Hershey, PA USA.
Hong-Gang
HG
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011758:Pyrroles; D013449:Sulfonamides; C528298:marinopyrrole A; D003630:Daunorubicin
ABT-737; Bcl-2; Mcl-1; acute myeloid leukemia; leukemia; maritoclax