Education

1976	M.S. Biological Sciences	Iowa State University | Ames, Iowa
1977	M.S. Molecular, Cellular, and Developmental Biology	Iowa State University Ames, Iowa
1980	PhD Molecular, Cellular, and Developmental Biology	Iowa State University Ames, Iowa

 

Biography

Professor Safa received his Bachelor of Science in Biology from the University of Esfahan, Iran, in 1973. He received his M.S. in General Biology in 1976, a M.S. in Molecular Cellular and Developmental Biology (MCDB) in 1977, and a Ph. D. in MCDB in 1980 from Iowa State University. He joined the University of Louisville as a Postdoctoral Fellow from 1980-1983, and subsequently was a Visiting Fellow and a guest researcher at the National Cancer Institute (NCI) from 1983-1987.

In 1987, he accepted a position as an Assistant Professor of Medicine at the University of Chicago and was Director of the Laboratories of Pharmacology and Pharmacokinetics, and Molecular Pharmacology, respectively in the Section of Hematology/Oncology from 1990-1996. In 1996, he accepted a tenured Associate Professor Position in the Department of Experimental Oncology, Medical University of South Carolina (MUSC), and was promoted to tenured Professor in 1999. Dr. Safa was Director of the Drug Resistance Program at Hollings Cancer Center at MUSC from 1998-1999. In 1999, he joined the faculty of the Indiana University School of Medicine as H.H. Gregg Professor of Cancer Research, and Professor of Pharmacology and Toxicology. Dr. Safa is also Director of the Graduate Program in the Department of Pharmacology and Toxicology.

Dr. Safa has been investigating the molecular and biochemical mechanisms of intrinsic and acquired resistance to chemotherapeutic drugs, apoptosis (cell death) in cancer cells, cancer stem cells, drug discovery and development, and cancer treatment. His lab is particularly interested in multi-targeted therapy of pancreatic tumors, brain cancer, and breast cancer through modulation of the death receptor signaling pathway in cancer cells. Currently, the laboratory is housed in the state of art Indiana University Simon Cancer Research Center (R3). He provides an outstanding environment and opportunity for training graduate students and postdoctoral fellows in the areas of molecular pharmacology, biochemistry, and cancer biology.

Dr. Safa served on the Experimental Therapeutics 1 Study Section at the NCI from 1988-2002, has been an Ad hoc Grant Reviewer, Center for Scientific Review, Drug Discovery and Molecular Pharmacology Study Section since 2003, Tumor cell Biology Study Section, and Department of Defense (DOD) since 2007. He has been a member of the Editorial Board of Molecular Cancer Therapeutics journal, World Journal of Pharmacology, Medicinal Chemistry, Journal of Drug Metabolism and Toxicology, International Journal of Biochemistry and Molecular Biology, Journal of Cell Death, Molecular Cancer Therapeutics, and Investigational New Drugs.

Research Interest

Targeting multiple signaling pathways in glioblastoma multiforme (GBM) and pancreatic cancer stem cells to eradicate these drug- and radiation-resistant cells; molecular mechanisms of drug-induced apoptosis; mechanisms of acquired resistance to cancer chemotherapeutic agents.

Professional Activities:

Teaching Activities:

1999- Present	Professor, Pharmacology and Toxicology, Indiana University
2003- 2007	Director of the Graduate Program, Indiana University
2002- 2006	Director, Graduate Program, Indiana University
1999	Professor, Medical Univ. of S. Carolina, South Carolina
1998- 1999	Assoc. Professor, Medical Univ. of S. Carolina, South Carolina
1996- 1997	Assoc. Professor, Medical Univ. of S. Carolina, South Carolina
1993- 1996	Asst. Professor, University of Chicago, Chicago, Illinois

Professional Activities:

• American Association for Cancer Research
• American Chemical Society
• American Society for Biochemistry and Molecular Biology
• Federation of American Societies for Experimental Biology

Publications

1. Safa AR, Stern RK, Choi K, Agresti M, Tamai I, Mehta ND, Roninson IB. Molecular basis of preferential resistance to colchicine in multidrug-resistant human cells conferred by Gly-1856Val-185 substitution in P-glycoprotein. Proc Natl Acad Sci USA 1990; 87:7225-7229.
2. Tamai I, Safa AR. Competitive interaction of cyclosporins with the Vinca alkaloid binding site of P-glycoprotein in multidrug resistant cells. J Biol Chem 1990; 265:16509-16513.
3. Samuels BL, Cohen MB, Safa AR, Sinha BK, Beckett MA, Weichselbaum RR. Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. Cancer Res 1991; 51:521-527.
4. Tamai I, Safa AR. Azidopine noncompetitively interacts with vinblastine and cyclosporin A binding to P-glycoprotein in multidrug resistant cells. J Biol Chem 1991; 266:16796-16800.
5. Fleming GF, Amato JM, Agresti M, Safa AR. Megestrol acetate reverses multidrug resistance and interacts with P-glycoprotein. Cancer Chemother Pharmacol 1992; 29:445-449.
6. Sinicrope FA, Dudeja PK, Bissonnette BM Safa AR, Brasitus TA. Modulation of Pglycoprotein mediated drug transport by alteration in lipid fluidity of rat liver canalicular membrane vesicles. J Biol Chem 1992; 267:24995-25002.
7. Rahman A, Husain SR, Siddiqui J, Verma M, Agresti M, Center M, Safa AR, Glazer RI. Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells. J Natl Cancer Inst 1992; 84:1909-1914.
8. Kajiji S, Talbot F, Grizzuti K, Van Dyke-Phillips V, Agresti M, Safa AR, Gros P. Functional analysis of P-glycoprotein mutants identifies predicted transmembrane domain 11 as a putative drug binding site. Biochemistry 1993; 32:4185-4194.
9. Samuels BL, Mick R, Vogelzang NJ, Williams SF, Schilsky RL, Safa AR, O'Brien S, and Ratain MJ. Modulation of vinblastine resistance with cyclosporine: A phase I study. Clin Pharmacol Ther 1993; 54:421-429.
10. Safa AR. Photoaffinity labeling of P-glycoprotein. Cancer Invest 1993; 11:46-56.
11. Safa AR, Agresti M, Bryk D, Tamai I. N-(p-azido-3[125I]iodo-phenethyl)Spiperone binds to specific regions of P-glycoprotein and another multidrug binding protein, Spiperophilin, in human neuroblastoma cells. Biochemistry 1994; 33:256-265.
12. Safa AR, Roberts S, Agresti M, Fine RL. Tamoxifen aziridine, a novel affinity probe for P-glycoprotein. Biochem Biophys Res Commun 1994; 202:606-612.
13. Krishnamachary N, Ma L, Zheng L, Safa AR, Center MS. Analysis of MRP gene expression and function in HL60 cells isolated for resistance to adriamycin. Oncol Res 1994; 6:119-127.
14. Ahmad S, Safa AR, Glazer RI. Modulation of P-glycoprotein activity by protein kinase C" in a baculovirus expression system. Biochemistry 1994; 33:10313-10318.
15. Benchekroun MN, Schneider E, Safa AR, Townsend AJ, Sinha BK. Mechanisms of resistance to ansamycin antibiotics in human breast cancer cell lines. Molec Pharmacol 1994; 46:677-684.
16. Sinicrope F, Hart J, Brasitus TA, Michelassi F, Lee JJ, Safa AR. Relationship of Pglycoprotein and carcinoembryonic antigen expression in human colon carcinoma to DNA ploidy, lymphovascular invasion and recurrence. Cancer 1994; 74:2908-2917.
17. Cano-Gauci DF, Seibert FS, Safa AR, Riordan JR. Selection and characterization of verapamil-resistant multidrug resistant cells. Biochem Biophys Res Commun 1995; 209:497-505.
18. Ogretmen B, Safa AR. Mini-preparation of total RNA for RT-PCR from cultured human cells. BioTechniques 1995; 19:374-376.
19. Sachs CW, Safa AR, Harrison SD, Fine RL. Inhibition of multidrug resistance by safingol with inhibition of protein kinase C independent of modulation of P-glycoprotein substrate activities. J Biol Chem 1995; 270:26639-26648.
20. Diamond AL, Jaffe D, Murray JL, Safa AR, Samuels BL, Hatfield DL. Lovastatin effects on human breast carcinoma cells. Differential toxicity of an adriamycin-resistant derivative and influence on selenocysteine tRNAs. Biochem Molec Biol Intl 1996; 38:345-355.
21. Gupta E, Safa AR, Wang X, Ratain MJ. Pharmacokinetic modulation of irinotecan and metabolites by cyclosporine A. Cancer Res 1996; 56:1309-1314.
22. Buckingham LE, Balasubramanian M, Safa AR, Shah H, Komarov P, Emanuele RM, Coon JS. Reversal of multi-drug resistance in vitro by fatty acid-PEG-fatty acid diesters. Int J Cancer 1996; 65:74-79.
23. Ogretmen B, Safa AR. Down-regulation of apoptosis-related bcl-2 but not bcl-XL or bax proteins in multidrug resistant MCF-7/Adr human breast cancer cells. Int J Cancer 1996; 67:1-7.
24. Sachs CW, Ballas L, Mascarella W, Safa AR, Lewin A, Loomis C, Carroll FI, Bell RM, Fine RL. Sphingosine stereoisomers inhibit multidrug resistance and protein kinase C activity without binding to vinblastine or azidopine binding sites on P-glycoprotein. Biochem Pharmacol 1996; 52:603-612.
25. Ogretmen B, Carpo C, Safa AR. Site-directed mutagenesis by unique site elimination using filamentous phage-derived ssDNA templates for plasmids that are resistant to denaturation. BioTechniques 1996; 21:209-213.
26. Lampidis TJ, Kalonias D, Podona T, Israel M, Safa AR, Lothstein L, Savaraj N, Tapiero H, Priebe W. Circumvention of P-glycoprotein-mediated multidrug resistance as a function of anthracycline lipophilicity and charge. Biochemistry 1997; 36:2679-2685.
27. Ogretmen B, Safa AR. Expression of the mutated p53 tumor suppressor protein and its molecular and biochemical characterization in multidrug resistant MCF-7/Adr human breast cancer cells. Oncogene 1997; 14:499-506.
28. Olopade OL, Adeyanju MO, Safa AR, Hagos F, Mick R, Thompson CB, Recant WR. Overexpression of the Bcl-X protein in primary human breast cancer is associated with high tumor grade and nodal metastases. Cancer J Sci Am 1997; 3:230-237.
29. Ogretmen B, Bahadori HR, McCauley MD, Boylan A, Green MR, Safa AR. Coordinated overexpression of the MRP and (γ-glutamylcysteine synthetase genes, but not MDR1, correlates with doxorubicin resistance in human malignant mesothelioma cell lines. Int J Cancer 1998; 75:757-761.
30. Frankel AE, Hall PD, McLain C, Safa AR, Tagge EP, Kreitman RJ. Cell-specific modulation of drug resistance in acute myeloid leukemic blasts by diphtheria fusion toxin DT388-GMCSF. Bioconjugate Chem 1998; 9:490-496.
31. Ogretmen B, McCauley MD, Safa AR. Molecular mechanisms of loss of β2-microglobulin expression in drug resistant breast cancer sublines and its involvement in drug resistance. Biochemistry 1998; 37:11679-11691.
32. Dolan ME, Frydman B, Thompson CB, Diamond AM, Garbiras BJ, Safa AR, Beck WT, Marton LJ. Effects of 1,2-naphthoquinones on human tumor cell growth and lack of cross-resistance with other anticancer agents. Anticancer Drugs 1998; 9:437-448.
33. Safa AR. Photoaffinity labels for characterization of drug interactions of P-glycoprotein. Methods Enzymol 1998; 292:289-307.
34. Ogretmen B, Bahadori HR, McCauley MD, Boylan A, Green MR, Safa AR. Lack of correlation of MRP and (γ-glutamylcysteine synthetase overexpression with doxorubicin resistance due to increased apoptosis in SV40 large T-antigen transformed human mesothelial cells. Cancer Chemother Pharmacol 1998; 42:441-446.
35. Ogretmen B, Safa AR. Negative regulation of MDR1 promoter activity in MCF-7, but not in multidrug resistant MCF-7/Adr cells, by cross-coupled NF-6B/p65 and c-Fos transcription factors and their interaction with the CAAT region. Biochemistry 1999; 38:2189-2199.
36. Rocha Lima CMS, Leong S-S, Sherman CA, Perkel JA, Putman-Hair T., Safa AR, Green MR. Phase I study of CPT-11 and gemcitabine in patients with solid tumors. Cancer Therapeutics 1999; 2:58-66.
37. Rocha Lima CMS, Eckardt JR, Leong S-S, Sherman CA, Perkel JA, Putman T, Safa AR, Bahadori HR, Green MR. Single-agent gemcitabine and gemcitabine/ irinotecan in nonsmall cell lung cancer. Semin Oncol 1999; 26:43-50.
38. Bahadori HR, Rocha Lima CMS, Green MR, Safa AR. Synergistic effect of gemcitabine and irinotecan (CPT-11) on breast and small cell lung cancer cell lines. Anticancer Res 1999; 19:5423-5428.
39. Safa AR. Photoaffinity analogs for multidrug resistance-related transporters. Drug Resistance Updates 1999; 2:371-381.
40. Ogretmen B, Barredo JC, Safa AR. Overexpression of LRP and MRP mRNAs in childhood acute lymphoblastic leukemia (ALL). J. Pediatric Oncol 2000; 22:45-49.
41. Ogretmen B, Safa AR. Identification and characterization of the MDR1 promoterenhancing factor 1 (MEF 1) in the multidrug resistant HL-60/VCR human acute myeloid leukemia cell line. Biochemistry 2000; 39:194-204.
42. Safa AR, Bahadori HR, Rocha Lima CMS, Green MR. Preclinical rationale for irinotecan and gemcitabine combination. Cancer Conference Highlights 2000; 4:4-6.
43. Rocha Lima, CMS, Safa AR, Green MR. Irinotecan and gemcitabine in combination (IrinoGem). Cancer Conference Highlights 2000; 4:7-10.
44. Green, MR., Harper, M., Safa, AR, Sherman, CA, Mushtaq, CM, Bahadori, H, Brescia, FJ, Rocha Lima, CMS. Irinotecan in the management of patients with pancreatic carcinoma. Oncology 2000; 14:31-33.
45. Wu C-H, Rastegar M. Gordon J, Safa AR. β2-microglobulin induces apoptosis in HL-60 human leukemia cell line and its multidrug resistant variants overexpressing MRP1 but lacking Bax or overexpressing P-glycoprotein. Oncogene 2001; 20:7006-7020.