title: Obatoclax potentiates the cytotoxic effect of cytarabine on acute myeloid leukemia cells by enhancing DNA damage.
abstract: Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression of Bcl-2, Bcl-xL, and/or Mcl-1 has been associated with chemoresistance in AML cell lines and with poor clinical outcome of AML patients. Thus, inhibitors of anti-apoptotic Bcl-2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations of obatoclax, a pan-Bcl-2 inhibitor, potentiate the antileukemic activity of cytarabine in AML cells. MTT assays in AML cell lines and diagnostic blasts, as well as flow cytometry analyses in AML cell lines revealed synergistic antileukemic activity between cytarabine and obatoclax. Bax activation was detected in the combined, but not the individual, drug treatments. This was accompanied by significantly increased loss of mitochondrial membrane potential. Most importantly, in AML cells treated with the combination, enhanced early induction of DNA double-strand breaks (DSBs) preceded a decrease of Mcl-1 levels, nuclear translocation of Bcl-2, Bcl-xL, and Mcl-1, and apoptosis. These results indicate that obatoclax enhances cytarabine-induced apoptosis by enhancing DNA DSBs. This novel mechanism provides compelling evidence for the clinical use of BH3 mimetics in combination with DNA-damaging agents in AML and possibly a broader range of malignancies.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, PR China.
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.affiliation: MD/PhD Program, Wayne State University School of Medicine, Detroit, MI, USA; Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Caldwell
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, PR China; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, PR China. Electronic address: gey@karmanos.org.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000494:pharmacology*; D004249:DNA Damage; D005260:Female; D006801:Humans; D007211:Indoles; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011758:Pyrroles / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D000964:Antimetabolites, Antineoplastic; D007211:Indoles; D011758:Pyrroles; D003561:Cytarabine; C520962:obatoclax
keywords: Acute myeloid leukemia; Cytarabine; DNA damage; Drug combination; Obatoclax