A novel Osmium-based compound targets the mitochondria and triggers ROS-dependent apoptosis in colon carcinoma

A Maillet,S Yadav,S Pervaiz,Y L Loo,K Sachaphibulkij

doi:10.1038/cddis.2013.185

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.

Highlights

It is well established that the redox status of the cell has a key role in cell fate
As autophagy has been linked to cell death in a variety of model systems, we set out to investigate whether autophagy had a central role in death induced by Os or was merely an associated event
We report the antitumoral activity of a new organometallic drug, a novel Os-based compound, on colon cancer cell lines by a mitochondria-targeting mechanism

Summary

Introduction

It is well established that the redox status of the cell has a key role in cell fate. Excessive accumulation of ROS from extra- or intramitochondrial sources could activate and/or amplify death execution, which provides a rationale for the design and development of redox-modifying small molecule compounds. In this regard, we recently reported the critical involvement of intracellular ROS in autophagy-associated apoptosis of human cancer cells by a novel small molecule.[15] Interestingly, a number of similar observations involving simultaneous induction of autophagy and apoptosis with other compounds have been reported,[16,17,18] and the precise role of autophagy during death execution is still being debated.[19]. Results show that Os induces changes in mitochondrial morphology and function, triggers apoptosis in a ROSdependent manner and inhibits tumor growth in a murine model of colon carcinogenesis

Methods

Results

Conclusion