Abstract
Abstract Demethylating agents remain one of the few options for treatment of AML in the elderly; however, the response rate is limited. In searching for p53 pathway activating agents for cancer therapy, we found that quinacrine is a potent p53 stimulator and induces tumor cell death. Quinacrine also induces expression of Death Receptor 5 (DR5), reduces expression of anti-apoptotic Mcl-1, and suppresses NFkB activity in tumor cells. Because of its acceptable toxicity profile, history of use in humans, and relevance of the target pathways modulated by quinacrine we explored whether it may serve as a potent anti-leukemia drug as most leukemia cells carry a wild-type p53. We tested the cytotoxic effects of quinacrine on malignant hematopoietic cell lines derived from patients with myeloid leukemia, including HL-60, MOLM-13, and MV4-11. We found that quinacrine induces massive cell death in the cell lines tested, at concentrations from as less as 1 microM to 5 microM, 2-10 times lower than required to induce solid tumor cell death. Most interestingly, quinacrine facilitates cell death in decitabine pre-treated leukemia cells in a synergistic manner. Further mechanistic studies showed that quinacrine stabilizes p53, induces Mcl-1 degradation, and PARP cleavage in treated cells. Our work supports translational efforts to advance the use of quinacrine from the bench to the clinic and provides a preliminary rationale for its combination with decitabine for the treatment of AML. Citation Format: Wenge Wang, David T. Dicker, David F. Claxton, Hong-Gang Wang, Wafik S. El-Deiry. Synergistic effect of quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cells in vitro: implication for treatment of AML in the elderly. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3486. doi:10.1158/1538-7445.AM2015-3486
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