Affiliations 

  • 1 Drug Discovery Laboratory, Cancer Research Initiatives Foundation (CARIF), Subang Jaya, Selangor, Malaysia; Department of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
  • 2 Department of Chemistry, Texas A & M University, College Station, Texas, United States of America
  • 3 Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 4 Department of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
  • 5 Drug Discovery Laboratory, Cancer Research Initiatives Foundation (CARIF), Subang Jaya, Selangor, Malaysia
PLoS ONE, 2014;9(3):e82934.
PMID: 24622277 DOI: 10.1371/journal.pone.0082934

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.