title: Discovery of a daunorubicin analogue that exhibits potent antitumor activity and overcomes P-gp-mediated drug resistance.
abstract: Anthracyclines are considered to be some of the most effective anticancer drugs for cancer therapy. However, drug resistance and cardiotoxicity of anthracyclines limit their clinical application. We hypothesize that direct modifications of the sugar moiety of anthracyclines avert P-glycoprotein (P-gp) recognition and efflux, increase drug intracellular concentration in cancer cells, and thus overcome P-gp-mediated drug resistance. Daunorubicin (DNR) analogues with sugar modifications were synthesized by directly transforming the amino group of DNR to an azido group or triazole group. Molecular docking showed that the lead compound (3'-azidodaunorubicin, ADNR) averts P-gp binding, while daunorubicin (DNR) extensively interacts with multidrug-resistance (MDR) protein through H-bonds and electrostatic interactions. FACS assay demonstrated that these new compounds abolished P-gp drug efflux and accumulated high intracellular concentration in the drug-resistant leukemia K562/Dox. P-gp inhibition by CsA confirmed that these new analogues are no longer P-gp substrates. ADNR exhibited potent anticancer activity in both drug-sensitive (K562) and drug-resistant leukemia cells (K562/Dox), with a 25-fold lower drug resistance index than DNR. An in vivo xenograft model demonstrated that ADNR showed more than 2.5-fold higher maximum growth inhibition rate against drug-resistant cancers and significant improvement for animal survival rate versus DNR. No significant body weight reduction in mice was observed for ADNR at the maximum tolerable dose, as compared to more than 70% body weight reduction for DNR. These data suggest that sugar modifications of anthracyclines avert P-gp binding, abolish P-gp-mediated drug efflux, increase intracellular drug concentration, and thus overcome P-gp-mediated drug resistance in cancer therapy.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Lanyan
authors.initials: L
authors.lastname: Fang
authors.forename: Guisheng
authors.initials: G
authors.lastname: Zhang
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Xincheng
authors.initials: X
authors.lastname: Zheng
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhu
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Xiao
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakacs
authors.forename: Janos
authors.initials: J
authors.lastname: Nadas
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
chemical_list: C508990:3'-azidodaunorubicin; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001386:Azides; D003630:Daunorubicin