All-trans retinoic acid synergizes with topotecan to suppress AML cells via promoting RARα-mediated DNA damage

BMC Cancer

Research Article

JinJin Shao¹  Peihua Luo¹  Qiaojun He¹  Zhifei Xu¹  Xueming Peng¹  Min Chen¹  Bo Yang¹  Guanqun Li¹  Lin Li¹  Hao Yan¹ 

[1] Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Zijingang Campus, 310058, Hangzhou, Zhejiang, People’s Republic of China;

关键词: AML;    Topotecan;    All-trans retinoic acid;    Apoptosis;    DNA damage;    RARα;   

DOI  :  10.1186/s12885-015-2010-6

 received in 2015-08-10, accepted in 2015-12-15,  发布年份 2016

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Xu et al. 2015