title: Rosamines targeting the cancer oxidative phosphorylation pathway.
abstract: Reprogramming of energy metabolism is pivotal to cancer, so mitochondria are potential targets for anticancer therapy. A prior study has demonstrated the anti-proliferative activity of a new class of mitochondria-targeting rosamines. This present study describes in vitro cytotoxicity of second-generation rosamine analogs, their mode of action, and their in vivo efficacies in a tumor allografted mouse model. Here, we showed that these compounds exhibited potent cytotoxicity (average IC50<0.5 µM), inhibited Complex II and ATP synthase activities of the mitochondrial oxidative phosphorylation pathway and induced loss of mitochondrial transmembrane potential. A NCI-60 cell lines screen further indicated that rosamine analogs 4 and 5 exhibited potent antiproliferative effects with Log10GI50 = -7 (GI50 = 0.1 µM) and were more effective against a colorectal cancer sub-panel than other cell lines. Preliminary in vivo studies on 4T1 murine breast cancer-bearing female BALB/c mice indicated that treatment with analog 5 in a single dosing of 5 mg/kg or a schedule dosing of 3 mg/kg once every 2 days for 6 times (q2d×6) exhibited only minimal induction of tumor growth delay. Our results suggest that rosamine analogs may be further developed as mitochondrial targeting agents. Without a doubt proper strategies need to be devised to enhance tumor uptake of rosamines, i.e. by integration to carrier molecules for better therapeutic outcome.
authors.affiliation: Drug Discovery Laboratory, Cancer Research Initiatives Foundation (CARIF), Subang Jaya, Selangor, Malaysia; Department of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Siang Hui
authors.initials: SH
authors.lastname: Lim
authors.affiliation: Department of Chemistry, Texas A & M University, College Station, Texas, United States of America.
authors.forename: Liangxing
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Lik Voon
authors.initials: LV
authors.lastname: Kiew
authors.affiliation: Department of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Lip Yong
authors.initials: LY
authors.lastname: Chung
authors.affiliation: Department of Chemistry, Texas A & M University, College Station, Texas, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Burgess
authors.affiliation: Drug Discovery Laboratory, Cancer Research Initiatives Foundation (CARIF), Subang Jaya, Selangor, Malaysia.
authors.forename: Hong Boon
authors.initials: HB
authors.lastname: Lee
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000588:Amines; D000970:Antineoplastic Agents