Research Knowledgebase

Niramol Savaraj, M.D. Professor of Medicine View full faculty profile

Description of Research

Small-cell lung cancer (SCLC) usually responds to chemotherapy, but relapse is inevitable. Although several new chemotherapeutic agents have shown activity in SCLC, salvage therapy is still poor. Research in Dr. Savaraj’s laboratory aims at identifying mechanism of resistance in SCLC and how to overcome them. Since combination of VP-16 and cisplatin is the most commonly used chemotherapeutic regimen in treating SCLC, Dr. Savaraj and her colleagues have studied the mechanism(s) of resistance of these two agents.

Dr. Savaraj’s laboratory has established two pairs of cisplatin-resistant sublines (SR-2 and BC) one VP-16-resistant subline (BV), one MRP1 (SCLCA), and one p-gp(SCLCR)-resistant subline from two parental line (SCLC1 and SCLCB). These cell lines were used to study mechanism(s) of resistance in SCLC. Using cDNA subtraction and microarray, she has found that both cisplatin-resistant cell lines overexpressed three group of cDNAs, the first group belongs to MMP family, the second group belongs to DNA damage and repair protein, and the third group belongs to translation. Upon review of the literature and data, the cDNA (s), which are consistently elevated, are the elongation factor and ribosomal protein. Since rapamycin or its analog CCI-779 can inhibit translation of mRNA encoding elongation factor, she has investigated these analogs for cisplatin reversal. The results revealed that all cell lines are sensitive to rapamycin and CCI-779 with the ID50 ranged from 0.05-0.1ug/ml. Furthermore, at 0.01ug/ml, both drugs can also restore cisplatin sensitivity three to five fold from ten to 15 fold and are able to completely restore VP-16 sensitivity in BV cell line. Neither rapamycin nor CCI-779 is able to reverse P-gp1 or MRP1 resistance. Based on these findings, Dr. Savaraj’s laboratory maintains three objectives:

• to study the mechanism(s) of mTOR inhibitor in reversal of cisplatin and VP-16 resistance
• to study the role of MMP in SCLC metastasis
• to develop clinical protocol using chemotherapy and mTor inhibitor

Cisplatin resistance
Cisplatin resistance is complex and involves several different mechanisms. By employing cDNA microarray analysis, researchers in this laboratory have found that cisplatin-resistant cells share an increase in ribosomal proteins and elongation factors. In order to survive cisplatin treatment, Dr. Savaraj and her colleagues believe that cells have to synthesize DNA repair proteins, antiapoptotic proteins, and growth-stimulating proteins. Thus, by blocking the translation of these proteins, cisplatin sensitivity can be restored. Researchers in this laboratory have studied the role of CCI-779, an ester analog of rapamycin which is known to inhibit translation by disabling mTOR, in restoring cisplatin sensitivity in a panel of cisplatin-resistant cell lines. This laboratory also has determined the role of CCI-779 in P-gp1 and MRP1- mediated resistance. Researchers’ data show that CCI-779 possesses anti-proliferative effects in both cisplatin-sensitive and resistant cell lines, but shows no effect in P-gp1 and MRP1 overexpressing cell lines. More importantly, CCI-779 at 10 ng/ml (less that ten percent of the growth inhibitory effect) can increase the growth inhibition of cisplatin by 2.5 to six fold. Moreover, CCI-779 also enhances the apoptotic effect of cisplatin in cisplatin-resistant cell lines. In these resistant cells, adding CCI-779 decreases the amount of 4E-BP phosphorylation and p-70S6kinase phosphorylation as well as lower the amount of elongation factor while cisplatin alone has no effect. However, CCI-779 can only reverse P-gp-mediated drug resistance at a higher dose(1 ug/ml).

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. PubMed link

Feun L, Savaraj N. Topoisomerase I inhibitors for the treatment of brain tumors. Expert Rev Anticancer Ther 8:707-16, 2008. PubMed link

Feun L, You M, Wu CJ, Kuo MT, Wangpaichitr M, Spector S, Savaraj N. Arginine deprivation as a targeted therapy for cancer. Curr Pharm Des 14:1049-57, 2008. PubMed link

Wangpaichitr M, Savaraj N, Maher J, Kurtoglu M, Lampidis TJ. Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines. Mol Cancer Ther 7:1506-13, 2008. PubMed link

Wangpaichitr M, Wu C, You M, Kuo MT, Feun L, Lampidis T, Savaraj N. Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur J Pharmacol 591:124-7, 2008. PubMed link

Chen HH, Song IS, Hossain A, Choi MK, Yamane Y, Liang ZD, Lu J, Wu LY, Siddik ZH, Klomp LW, Savaraj N, Kuo MT. Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1. Mol Pharmacol 74:697-704, 2008. PubMed link

Kuo MT,Chen HH,Song IS,Savaraj N,Ishikawa T. The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26:71-83,2007. PubMed link

Maher JC, Wangpaichitr M, Savaraj N, Kurtoglu M, Lampidis TJ. Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose. Mol Cancer Ther 6:732-41,2007. PubMed link

Dinh V,Feun L,Elgart G,Savaraj N. Merkel cell carcinomas. Hematol Oncol Clin North Am 21:527-44,2007. PubMed link

Feun LG, Marini A, Landy H, Markoe A, Heros D, Robles C, Herrera C, Savaraj N. Clinical trial of CPT-11 and VM-26/VP-16 for patients with recurrent malignant brain tumors. J Neurooncol 82:177-81, 2007. PubMed link

For full description of Multidisciplinary Research Program(s), Molecular Therapeutics Program.