Obatoclax potentiates the cytotoxic effect of cytarabine on acute myeloid leukemia cells by enhancing DNA damage

• DOI: 10.1016/j.molonc.2014.09.008
• Publication Date: 2014-10-03T22:40:52Z
• Authors: Chengzhi Xie; Holly Edwards; J. Timothy Caldwell; Guan Wang; Jeffrey W. Taub; Yubin Ge
• Keywords: Male; Antimetabolites, Antineoplastic; 0303 health sciences; Indoles; Cytarabine; U937 Cells; 3. Good health; Leukemia, Myeloid, Acute; 03 medical and health sciences; Child, Preschool; Humans; Female; Pyrroles; Child; DNA Damage

Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression Bcl-2, Bcl-xL, and/or Mcl-1 has been associated with chemoresistance in AML cell lines poor clinical outcome Thus, inhibitors anti-apoptotic Bcl-2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations obatoclax, pan-Bcl-2 inhibitor, potentiate the antileukemic activity cells. MTT assays diagnostic blasts, as well flow cytometry analyses revealed synergistic between obatoclax. Bax activation was detected combined, but not individual, drug treatments. This accompanied by significantly increased loss mitochondrial membrane potential. Most importantly, cells treated combination, enhanced early induction DNA double-strand breaks (DSBs) preceded decrease levels, nuclear translocation Mcl-1, apoptosis. These results indicate that obatoclax enhances cytarabine-induced apoptosis enhancing DSBs. mechanism provides compelling evidence use BH3 mimetics combination DNA-damaging agents possibly broader range malignancies.