Rosamines Targeting the Cancer Oxidative Phosphorylation Pathway

• DOI: 10.1371/journal.pone.0082934
• Publication Date: 2014-03-12T20:21:47Z
• Authors: Siang Hui Lim; Liangxing Wu; Lik Voon Kiew; Lip Yong Chung; Kevin Burgess; Hong Boon Lee
• Keywords: Science; Q; R; Antineoplastic Agents; Xenograft Model Antitumor Assays; Oxidative Phosphorylation; Mitochondria; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Medicine; Animals; Humans; Female; Molecular Targeted Therapy; Amines; Research Article

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 a new class mitochondria-targeting rosamines. This present describes in vitro cytotoxicity second-generation rosamine analogs, their mode action, and vivo efficacies tumor allografted mouse model. Here, we showed that these compounds exhibited potent (average IC50<0.5 µM), inhibited Complex II ATP synthase activities mitochondrial oxidative phosphorylation pathway induced loss transmembrane potential. NCI-60 cell lines screen further indicated analogs 4 5 antiproliferative effects with Log10GI50 = −7 (GI50 0.1 µM) were more effective against colorectal cancer sub-panel than other lines. Preliminary studies on 4T1 murine breast cancer-bearing female BALB/c mice treatment analog single dosing mg/kg or schedule 3 once every 2 days 6 times (q2d×6) only minimal induction growth delay. Our results suggest may be developed as targeting agents. Without doubt proper strategies need devised enhance uptake rosamines, i.e. by integration carrier molecules better therapeutic outcome.