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Rosamines targeting the cancer oxidative phosphorylation pathway

Lim, Siang Hui ; Wu, Liangxing ; Kiew, Lik Voon ; Chung, Lip Yong ; Burgess, Kevin ; Lee, Hong Boon Pandey, Siyaram

PloS one, 2014-03, Vol.9 (3), p.e82934-e82934 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Rosamines targeting the cancer oxidative phosphorylation pathway
Autor: Lim, Siang Hui ; Wu, Liangxing ; Kiew, Lik Voon ; Chung, Lip Yong ; Burgess, Kevin ; Lee, Hong Boon
Pandey, Siyaram
Assuntos: Amines - chemistry ; Amines - pharmacology ; Analogs ; Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Biology ; Cancer ; Cancer therapies ; Cancer treatment ; Care and treatment ; Cell cycle ; Cell Line, Tumor ; Chemistry ; Chemotherapy ; Colorectal cancer ; Deoxyribonucleic acid ; DNA ; Drugs ; Female ; Humans ; Laboratory animals ; Medical research ; Medical screening ; Medicine ; Mice ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Molecular Targeted Therapy ; Muridae ; Oxidative Phosphorylation - drug effects ; Pharmacy ; Phosphorylation ; Physiological aspects ; Polyethylene glycol ; Potassium ; R&D ; Research & development ; Rodents ; Xenograft Model Antitumor Assays
É parte de: PloS one, 2014-03, Vol.9 (3), p.e82934-e82934
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: SHL HBL LYC. Performed the experiments: SHL LW. Analyzed the data: SHL LVK. Contributed reagents/materials/analysis tools: HBL KB LVK LYC. Wrote the paper: SHL KB HBL.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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Rosamines targeting the cancer oxidative phosphorylation pathway

Lim, Siang Hui ; Wu, Liangxing ; Kiew, Lik Voon ; Chung, Lip Yong ; Burgess, Kevin ; Lee, Hong Boon Pandey, Siyaram

United States: Public Library of Science

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