Abstract
BackgroundChemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more effective and less toxic.MethodsMTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis.ResultsWe found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model.ConclusionsOur data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-2010-6) contains supplementary material, which is available to authorized users.
Highlights
Chemotherapy is the only therapy option for the majority of Acute myeloid leukemia (AML) patients, there are several limitations for this treatment
Our study provides molecular insights for apoptosis involving TPT and all-trans retinoic acid (ATRA) by demonstrating that ATRA helps TPT cause serious DNA damage leading the AML cells HL60 to apoptosis, and RARα is involved in this process
TPT and ATRA synergistically induce a cytotoxic effect in AML cells To evaluate the potential synergy between ATRA and the Topoisomerase1 inhibitor TPT, cells (HL60, NB4 and U937) were exposed for 48 h to increasing concentrations of TPT (0, 20, 40, 60, 80 nM) alone or in combination with ATRA at a concentration that reduces cell viability according to data from preclinical research and our laboratory
Summary
Chemotherapy is the only therapy option for the majority of AML patients, there are several limitations for this treatment. Acute myeloid leukemia (AML) is the most common acute leukemia worldwide and has high mortality rates, the overall median survival for patients with AML is 6.5 months due to limited treatment choices [1, 2]. The current treatment options for patients with AML are bone marrow transplants, radiofrequency ablation and chemotherapy [3]. Bone marrow transplants are only curative for a small percentage of matching patients [4]. The efficacy or response rate of radiofrequency ablation in advanced AML is pretty low [5]. Chemotherapy, the only or necessary choice for most AML patients, is often limited by toxicities [6]. It is critical to discover effective drug treatments for AML patients
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