title: Identification of 5-Iodotubercidin as a genotoxic drug with anti-cancer potential.
abstract: Tumor suppressor p53, which is activated by various stress and oncogene activation, is a target for anti-cancer drug development. In this study, by screening panels of protein kinase inhibitors and protein phosphatase inhibitors, we identified 5-Iodotubercidin as a strong p53 activator. 5-Iodotubercidin is purine derivative and is used as an inhibitor for various kinases including adenosine kinase. We found that 5-Iodotubercidin could cause DNA damage, verified by induction of DNA breaks and nuclear foci positive for γH2AX and TopBP1, activation of Atm and Chk2, and S15 phosphorylation and up-regulation of p53. As such, 5-Iodotubercidin induces G2 cell cycle arrest in a p53-dependent manner. Itu also induces cell death in p53-dependent and -independent manners. DNA breaks were likely generated by incorporation of 5-Iodotubercidin metabolite into DNA. Moreover, 5-Iodotubercidin showed anti-tumor activity as it could reduce the tumor size in carcinoma xenograft mouse models in p53-dependent and -independent manners. These findings reveal 5-Iodotubercidin as a novel genotoxic drug that has chemotherapeutic potential.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Deyong
authors.initials: D
authors.lastname: Jia
authors.forename: Huijuan
authors.initials: H
authors.lastname: Liu
authors.forename: Na
authors.initials: N
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.forename: Bin
authors.initials: B
authors.lastname: Hao
authors.forename: Daxiang
authors.initials: D
authors.lastname: Cui
authors.forename: Yuezhen
authors.initials: Y
authors.lastname: Deng
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004249:DNA Damage; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D009153:Mutagens / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; C034214:5-iodotubercidin; D064007:Ataxia Telangiectasia Mutated Proteins; D014372:Tubercidin