Niramol Savaraj, M.D.
Professor of Medicine
Description of Research
Cisplatin resistance remains a major obstacle in the treatment of both small cell and non-small cell lung cancer. Due to its complexity, which involves multiple mechanisms, cisplatin resistance is difficult to overcome. We have discovered that cisplatin resistant (CR) cells share one common biochemical parameter, which is an increase in reactive oxygen species (ROS). Thus, further increased ROS in these CR cells can push them beyond their tolerance limit, which ultimately leads to cell death. Indeed, our initial data have shown that elesclomol, an agent which is known to increase ROS, is significantly more cytotoxic toward CR cells with the ID50 dosage of 4-10 fold less than their parental cell counterparts or normal cells. Elesclomol also has unique action by bringing in copper to mitochondria and results in increasing ROS. Tumor cells which are not resistant to cisplatin are not sensitive to this agent. Interestingly, these CR cells derived their energy source from amino acids and fatty acids instead of glucose as carbon source for bioenergetic and biosynthesis. Overall, this work will serve as a novel approach to overcome cisplatin resistance by exploiting the primary biochemical differences, which these resistant cells adopt to survive. Thus, by targeting these differences, we can selectively kill these resistant cells with minimal normal tissue toxicity.
- Cisplatin-resistant cell lines have higher basal ROS when compared to their parental cell counterparts.
- Further increased ROS in these cisplatin resistant cells can push them beyond their tolerance limit, which ultimately leads to cell death.
- Elesclomol induced ROS production and is highly cytotoxic to cisplatin-resistant lines.
Selected Cancer-Related Publications
- Liang ZD, Stockton D, Savaraj N, Tien Kuo M. Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin. Mol Pharmacol 76:843-53,2009. Read more »
Collaborating in the Multidisciplinary Research Program(s):