TY - JOUR T1 - Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistances JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.243451 SP - jpet.117.243451 AU - Feihong Chen AU - Gang Xu AU - Xiaodong Qin AU - Xiufeng Jin AU - Shaohua Gou Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/09/15/jpet.117.243451.abstract N2 - Two hybrids were designed and prepared by addition of a chlorambucil unit to an axial position of the Pt(IV) complex derived from DN603 or DN604 which was recently found to exhibit significant anticancer activity and low toxicity. Cytotoxicity of two compounds 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 drugs resistances. Mechanistic investigation suggested that the potent antitumor activity of 5 arose from its major suppression of CK2-mediated MRE11-RAD50-NBS1(MRN) complex promotion of DNA double-strand breaks (DSBs) repair. In nude mice with A549/cDDP xenografts, 5 exhibited higher anticancer efficacy than cisplatin and chlorambucil via reversing drug resistance, displayed improved effectiveness and had hardly toxicity effects in contrast to DN604. Overall, 5 is a promising drug candidate, which could promote the anticancer activity and reverse drug resistance via attenuating CK2-induced MRN-dependent DSBs repair. ER -