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Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistance.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2017 Nov; Vol. 363 (2), pp. 221-239. Date of Electronic Publication: 2017 Sep 15. - Publication Year :
- 2017
-
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.<br /> (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)
- Subjects :
- Animals
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents, Alkylating pharmacokinetics
Calcium metabolism
Casein Kinase II antagonists & inhibitors
Cell Line, Tumor
Chlorambucil pharmacokinetics
Cisplatin pharmacology
DNA Repair drug effects
Drug Design
Female
Humans
Male
Mice
Mice, Inbred BALB C
Platinum metabolism
Platinum Compounds pharmacokinetics
Rats, Sprague-Dawley
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Antineoplastic Agents, Alkylating pharmacology
Chlorambucil pharmacology
DNA, Neoplasm drug effects
Drug Resistance, Neoplasm drug effects
Platinum Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 363
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 28916659
- Full Text :
- https://doi.org/10.1124/jpet.117.243451