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

Kenichiro Doi, Qiang Liu, Krishne Gowda, Brian M. Barth, David Claxton, Shantu Amin, Thomas P. Loughran, Hong-Gang Wang

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1077-1086
Number of pages10
JournalCancer Biology and Therapy
Volume15
Issue number8
DOIs
StatePublished - Jan 1 2014

Fingerprint

Myeloid Cells
Acute Myeloid Leukemia
Apoptosis
Daunorubicin
Nude Mice
Bone Marrow Cells
Down-Regulation
Poisons
Multiple Drug Resistance
Hematopoietic Stem Cells
Blood Cells
Neoplasms
Leukemia
Cell Death
Therapeutics
marinopyrrole A
Recurrence
Cell Line
Pharmaceutical Preparations
ABT-737

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

@article{fd1c204acc744c339970776ab430d0da,
title = "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.",
author = "Kenichiro Doi and Qiang Liu and Krishne Gowda and Barth, {Brian M.} and David Claxton and Shantu Amin and Loughran, {Thomas P.} and Hong-Gang Wang",
year = "2014",
month = "1",
day = "1",
doi = "10.4161/cbt.29186",
language = "English (US)",
volume = "15",
pages = "1077--1086",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Landes Bioscience",
number = "8",

}

Maritoclax induces apoptosis in acute myeloid leukemia cells with elevated Mcl-1 expression. / Doi, Kenichiro; Liu, Qiang; Gowda, Krishne; Barth, Brian M.; Claxton, David; Amin, Shantu; Loughran, Thomas P.; Wang, Hong-Gang.

In: Cancer Biology and Therapy, Vol. 15, No. 8, 01.01.2014, p. 1077-1086.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Maritoclax induces apoptosis in acute myeloid leukemia cells with elevated Mcl-1 expression

AU - Doi, Kenichiro

AU - Liu, Qiang

AU - Gowda, Krishne

AU - Barth, Brian M.

AU - Claxton, David

AU - Amin, Shantu

AU - Loughran, Thomas P.

AU - Wang, Hong-Gang

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84905439095&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905439095&partnerID=8YFLogxK

U2 - 10.4161/cbt.29186

DO - 10.4161/cbt.29186

M3 - Article

C2 - 24842334

AN - SCOPUS:84905439095

VL - 15

SP - 1077

EP - 1086

JO - Cancer Biology and Therapy

JF - Cancer Biology and Therapy

SN - 1538-4047

IS - 8

ER -