title: A novel Osmium-based compound targets the mitochondria and triggers ROS-dependent apoptosis in colon carcinoma.
abstract: Engagement of the mitochondrial-death amplification pathway is an essential component in chemotherapeutic execution of cancer cells. Therefore, identification of mitochondria-targeting agents has become an attractive avenue for novel drug discovery. Here, we report the anticancer activity of a novel Osmium-based organometallic compound (hereafter named Os) on different colorectal carcinoma cell lines. HCT116 cell line was highly sensitive to Os and displayed characteristic features of autophagy and apoptosis; however, inhibition of autophagy did not rescue cell death unlike the pan-caspase inhibitor z-VAD-fmk. Furthermore, Os significantly altered mitochondrial morphology, disrupted electron transport flux, decreased mitochondrial transmembrane potential and ATP levels, and triggered a significant increase in reactive oxygen species (ROS) production. Interestingly, the sensitivity of cell lines to Os was linked to its ability to induce mitochondrial ROS production (HCT116 and RKO) as HT29 and SW620 cell lines that failed to show an increase in ROS were resistant to the death-inducing activity of Os. Finally, intra-peritoneal injections of Os significantly inhibited tumor formation in a murine model of HCT116 carcinogenesis, and pretreatment with Os significantly enhanced tumor cell sensitivity to cisplatin and doxorubicin. These data highlight the mitochondria-targeting activity of this novel compound with potent anticancer effect in vitro and in vivo, which could have potential implications for strategic therapeutic drug design.
authors.affiliation: ROS, Apoptosis and Cancer Biology Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Maillet
authors.forename: S
authors.initials: S
authors.lastname: Yadav
authors.forename: Y L
authors.initials: YL
authors.lastname: Loo
authors.forename: K
authors.initials: K
authors.lastname: Sachaphibulkij
authors.forename: S
authors.initials: S
authors.lastname: Pervaiz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004789:Enzyme Activation; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology*; D009992:Osmium; D017382:Reactive Oxygen Species / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D009992:Osmium; D020169:Caspases