title: All-trans retinoic acid synergizes with topotecan to suppress AML cells via promoting RARα-mediated DNA damage.
abstract: BACKGROUND
  Chemotherapy 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.
  
  
  METHODS
  MTT 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Xu
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China.
authors.forename: JinJin
authors.initials: J
authors.lastname: Shao
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China.
authors.forename: Xueming
authors.initials: X
authors.lastname: Peng
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China.
authors.forename: Guanqun
authors.initials: G
authors.lastname: Li
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yan
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China. peihualuo@zju.edu.cn.
authors.forename: Peihua
authors.initials: P
authors.lastname: Luo
authors.affiliation: 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, Hangzhou, 310058, Zhejiang, People's Republic of China. qiaojunhe@zju.edu.cn.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D019772:Topotecan / Q000008:administration & dosage*; D014212:Tretinoin / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000607071:RARA protein, human; D034741:RNA, Small Interfering; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D019772:Topotecan