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Abstract
Two hybrids of Pt(IV) species were designed and prepared by addition of a chlorambucil unit to the axial positions of the Pt(IV) complexes derived from DN603 and DN604. In vitro studies of two hybrids against two pairs of cisplatin sensitive and resistant cancer cell lines indicated that compound 5 had superior antitumor activity to cisplatin and chlorambucil via suppressing DNA damage repair to reverse drug resistance. Mechanistic investigation suggested that the potent antitumor activity of compound 5 arose from its major suppression of CK2-mediated MRE11-RAD50-NBS1(MRN) complex promotion of DNA double-strand break (DSB) repair. In nude mice with A549/CDDP xenografts, compound 5 exhibited higher anticancer efficacy than cisplatin and chlorambucil by reversing drug resistance, displayed improved effectiveness, and had no toxicity effects. Overall, compound 5 is a promising drug candidate, which could promote the anticancer activity and reverse drug resistance by attenuating CK2-induced MRN-dependent DSB repair.
Footnotes
- Received June 21, 2017.
- Accepted September 11, 2017.
↵1 F.C. and G.X. contributed equally to this article.
We are grateful to the National Natural Science Foundation of China [Grant 21571033 and 81503099] for financial aid for this work. The research was also supported by Jiangsu Province Natural Science Foundation [Grant BK20150643].
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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