Sylvester Comprehensive Cancer Center

Niramol Savaraj, M.D.

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.

Highlights

  • 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, Long Y, Chen HH, Savaraj N, Kuo MT. Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals. J Biol Inorg Chem :,2013 Read more »
  • You M, Varona-Santos J, Singh S, Robbins DJ, Savaraj N, Nguyen DM. Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro. J Thorac Cardiovasc Surg :,2013 Read more »
  • Liang ZD, Long Y, Tsai WB, Fu S, Kurzrock R, Gagea-Iurascu M, Zhang F, Chen HH, Hennessy BT, Mills GB, Savaraj N, Kuo MT. Mechanistic Basis for Overcoming Platinum Resistance Using Copper Chelating Agents. Mol Cancer Ther :,2012 Read more »
  • Kuo MT, Fu S, Savaraj N, Chen HH. Role of the human high-affinity copper transporter in copper homeostasis regulation and Cisplatin sensitivity in cancer chemotherapy. Cancer Res 72:4616-21,2012 Read more »
  • Tsai WB, Aiba I, Long Y, Lin HK, Feun L, Savaraj N, Kuo MT. Activation of Ras/PI3K/ERK Pathway Induces c-Myc Stabilization to Upregulate Argininosuccinate Synthetase,Leading to Arginine Deiminase Resistance in Melanoma Cells. Cancer Res 72:2622-33,2012 Read more »
  • Wangpaichitr M, Sullivan EJ, Theodoropoulos G, Wu C, You M, Feun LG, Lampidis TJ, Kuo MT, Savaraj N. The Relationship of Thioredoxin-1 and Cisplatin Resistance: Its Impact on ROS and Oxidative Metabolism in Lung Cancer Cells. Mol Cancer Ther 11:604-15,2012 Read more »
  • Feun LG, Marini A, Walker G, Elgart G, Moffat F, Rodgers SE, Wu CJ, You M, Wangpaichitr M, Kuo MT, Sisson W, Jungbluth AA, Bomalaski J, Savaraj N. Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase. Br J Cancer 106:1481-5,2012 Read more »
  • You M, Savaraj N, Kuo MT, Wangpaichitr M, Varona-Santos J, Wu C, Nguyen DM, Feun L. TRAIL induces autophagic protein cleavage through caspase activation in melanoma cell lines under arginine deprivation. Mol Cell Biochem :,2012 Read more »
  • Xi H, Kurtoglu M, Liu H, Wangpaichitr M, You M, Liu X, Savaraj N, Lampidis TJ. 2-Deoxy-D: -glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemother Pharmacol 67:899-910,2011 Read more »
  • Kuo MT, Savaraj N, Feun LG. Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. Oncotarget 1:246-251,2010 Read more »
  • Sasine JP, Savaraj N, Feun LG. Topoisomerase I Inhibitors in the Treatment of Primary CNS Malignancies: An Update on Recent Trends. Anticancer Agents Med Chem 10:683-696,2010 Read more »

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