Open AccessIdentification of 5-Iodotubercidin as a Genotoxic Drug with Anti-Cancer Potential
Author(s) -
Xin Zhang,
Dongyu Jia,
Huijuan Liu,
Na Zhu,
Wei Zhang,
Jun Feng,
Jun Yin,
Bin Hao,
Daxiang Cui,
Yuezhen Deng,
Dong Xie,
Lin He,
Baojie Li
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0062527
Subject(s) - adenosine kinase , dna damage , biology , cancer research , dna repair , kinase , protein kinase a , microbiology and biotechnology , dna , adenosine , biochemistry , adenosine deaminase
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.