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Postdoctoral Education
| Institution |
Level (Intern,
Resident, Fellow) |
Year |
| Department of Helath Services, Lab Field Services |
Clinical Lab Scientist (CLS) |
1997 |
| University of California, Los Angeles |
PhD. Tumor Immunology |
2003 |
| UCLA, Microbiology, Immunology, Molecular Genetics |
Postdoctoral Fellow |
2003-2004 |
| Howard Hughes Medical Institute (HHMI) |
Associate |
2004-2008 |
| UCLA Surgical Oncology |
Assistant Researcher |
2008-2009 |
Honors and Awards
2009 Scholar-in-Training Award
American Association for Cancer Research, AACR-Merck
2008 Certificate of Merit
American Association of Bioanalysts (AAB)
2005 Award of Excellence
American Society of Hematology (ASH)
2005 “Needs and Merits” Award
American Society of Hematology (ASH)
Research Interests
The vast majority of anticancer agents eradicate tumor cells by apoptosis. Tumors, in turn, have adopted various mechanisms to evade apoptosis. For instance natural inhibitors of apoptosis, such as Bcl-2 and IAP family members protect the tumor cells from the apoptotic effects of various antineoplastic agents via different mechanisms. Thus, as tumor cells develop resistance to drugs, they may also develop cross-resistance to the cytotoxic effects of the immune system. The development of cross-resistance suggests that drugs and cytotoxic ligands utilize a common apoptotic pathway. Another major challenge is posed by cancer stem cells, which are believed to be responsible for recurrences and metastases. Thus, nontoxic agents that adversely modulate the signaling pathways leading to modulation of the expression profile of apoptosis-associated gene products can be effectively used in combination with chemotherapy and/or immunotherapy in the treatment of resistant tumors.
The other issue concerning apoptosis resistance is often due to the failure of cells to carry out the signal transduction pathways ultimately leading to cell death. This may be due to insufficient expression of signaling molecules, overexpression of protective factors, mutations in anti-apoptotic proteins, or transcriptional silencing of pro-apoptotic factors. Drugs are capable of regulating the expression levels of anti- and pro-apoptotic proteins illustrating the possibility that therapeutic compounds may not directly induce cytotoxicity but nonetheless possess the ability to alter protein expression profile in a manner that would allow additional agents to induce apoptosis at much lower threshold, thus, not only minimizing the undesired toxic side effects but also induce synergistic killing of tumor cells. Thus, the direct cytotoxicity and sensitizing attributes exerted by drugs are accomplished via distinct mechanisms although some overlap may exist.
The long-term goal of my laboratory is to focus on determination of the major signaling pathways responsible for apoptosis-resistance which can be regulated by sensitizing agents, thus, averting the resistant phenotype of drug-refractory tumors. Specific examples of the target molecules include MEK1/2 in the Ras-ERK1/2 pathway, PTEN and AKT in the PKB pathway and Apaf-1 in type II apoptosis pathway. To this end, the functional complementation (Sensitization) model is proposed, whereby treatment of tumor cells with a nontoxic sensitizing agent alters the expression profile of apoptosis-associated gene products (signal I), removes the inhibitory block in the apoptotic pathway and by lowering the apoptosis threshold sensitizes the tumor cells to the killing effects of the second agent (e.g., cytotoxic ligands, biological response modifiers and/or chemo-therapeutic drugs) (signal II). The functional complementation model further attests to the contention that therapeutic compounds, in addition to the ability to directly induce apoptosis, are capable of altering the gene expression profile and decrease the apoptosis threshold of drug-resistant tumor cells, thus, overcoming the acquired or intrinsic apoptosis-resistance. Delineation of signaling pathways modulated by specific agents will reveal intracellular targets for therapeutic intervention in the treatment of refractory tumors. Further, based on the genetic profile of tumors and identification of the targets that control response to treatment, it is possible to identify cancer patients for alternative therapeutic intervention to circumvent the resistant phenotype (molecular signatures).
Academic/Teaching Appointments
- Assistant Professor, Surgical Oncology-Melanoma Immunotherapy- UCLA School of Medicine
Publications
1. Stavroula Baritaki, Eriko Suzuki, Kazuo Umezawa, Demetrios A. Spandidos, James Berenson, Tracy R. Daniels, Manuel L. Penichet, Ali R. Jazirehi, Michael Palladino, Benjamin Bonavida. Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells. Journal of Immunology. 180: 6199-210, 2008.
2. Mario I Vega, Melissa Martinez-Paniagua, Ali R. Jazirehi, Sara Huerta-Yepez, Umezawa K, Martinez-Maza O, Benjamin Bonavida. The NF-kappaB inhibitors (bortezomib and DHMEQ) sensitise rituximab-resistant AIDS-B-non-Hodgkin’s lymphoma to apoptosis by various chemotherapeutic drugs. Leuk Lymphoma. 49 (10):1982-94, 2008.
3. Ali R. Jazirehi, Mario I. Vega, Benjamin Bonavida. Development of rituximab-resistant lymphoma clones with altered cell signaling and cross-resistance to chemotherapy: circumvention of acquired resistance by specific pharmacological inhibitors. Cancer Research, 67 (3):1270-1281, 2007.
4. Jian Xu, Scott D. Pope, Ali R. Jazirehi, Joanne L. Attema, Peter Papathanasiou, Jason Watts, Kenneth S. Zaret, Irving L. Weissman, Stephen T. Smale. Pioneer Factor Interactions and Unmethylated CpG Dinucleotides Mark Silent Tissue-Specific Enhancers in Embryonic Stem Cells. Proc. Natl. Acad Science, 104: 12377-12382, 2007.
5. Ali R. Jazirehi, Sara Huerta, Genhong Cheng, Benjamin Bonavida. Rituximab (chimeric anti-CD20 mAb) inhibits the constitutive NF-κB signaling pathway in non-Hodgkin’s lymphoma (NHL) B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Research, 65 (1): 264 -276, 2005.
6. Ali R. Jazirehi, and Benjamin Bonavida. Molecular and Cellular Signal Transduction Pathways Modulated by Rituximab (Rituxan, anti-CD20 mAb) in Non-Hodgkin’s Lymphoma: Implications in Chemo-sensitization and Therapeutic (Review). Oncogene, 24 (13): 2121-2143, 2005.
7. Mario I. Vega*, Ali R. Jazirehi*, Sara Huerta-Yepez*, Benjamin Bonavida. Rituximab-induced inhibition of YY1 and Bcl-xL expression in Ramos Non-Hodgkin’s lymphoma cell line via inhibition of NF-B acitivity: role of YY1 and Bcl-xL expression in Fas resistance and chemoresistance, respectively. Journal of Immunology, 175: 2174-2183, 2005.
8. Mario I Vega1, Sara Huerta-Yepez, Ali R Jazirehi, Hermes Garban, Benjamin Bonavida. Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced Apoptosis. Oncogene, 24 (55): 8114-27, 2005.
9. Fumiya Hongo, Sara Huerta-Yepez, Mario Vega, Hermes Garban, Ali R Jazirehi, Yoichi Mizutani, Tsuneharu Miki, Benjamin Bonavida. Inhibition of YY1 activity by S-nitrosation. Biochem. Biophys. Research Communications, 336 (2): 692-701, 2005.
10. Ali R. Jazirehi, Benjamin Bonavida. Resveratrol modifies the expression of apoptotic regulatory gene products and sensitizes non-Hodgkin's lymphoma and multiple myeloma cells to to paclitaxel-induced apoptosis. Mol Cancer Ther., 3(1) 71-84, 2004.
11. Mario Vega, Sara Huerta, Ali R. Jazirehi, Hermes Garban, Christos Emmanouilides, Benjamin Bonavida. Rituximab inhibits p38MAPK activity in 2F7 NHL B-cells and results in inhibition of IL-10 transcription: pivotal role of p38MAPK in drug-resistance. Oncogene, 23: 3530-3540, 2004.
12. Golaun Odabaie, Devasis Chatterjee, Ali R. Jazirehi, Lee Goodglick, Kam Yeung, Benjamin Bonavida. Raf Kinase inhibitor (RKIP): structure, function, regulation of cell signaling and apoptosis. Advances in Cancer Research, 91: 169-200, 2004.
13. Ali R. Jazirehi, Mario Vega, Devasis Chatterjee, Lee Goodglick, Benjamin Bonavida. Inhibition of the Raf–MEK1/2–ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin’s lymphoma B-cells by Rituximab. Cancer Research 64 (19): 7117-7126, 2004.
14. Sara Huerta, Mario Vega, Ali R. Jazirehi, Hermes Garban, Fumiya Hongo, Genhong Cheng, Benjamin Bonavida. Nitric oxide sensitizes prostate carcinoma cell lines to TRAIL-mediated apoptosis via inactivation of NF-B and inhibition of Bcl-xL expression. Oncogene, 23: 4993-5003, 2004.
15. Ali R. Jazirehi, Gan X-H, De Vos S, Emmanouilides C, Bonavida B. Rituximab (anti-CD20) selectively modifies Bcl-xL and Apaf-1 expression and sensitizes human Non-Hodgkin’s Lymphoma B cell lines to paclitaxel-induced apoptosis. Mol. Cancer Therapeutics, 2: 1183-1193, 2003.
16. Sergio Huerta, Jonas Hannestad, Ali R. Jazirehi, Benjamin Bonavida, Diane Harris, Ronald W. Irwin, David Heber, David Elashoff, Edward H. Livingston. Gene expression profile of metastatic colon cancer cells resistant to cisplatin-induced apoptosis. Int. J. Oncology, 22(3): 671, 2003.
17. Corwin Hansch, Benjamin Bonavida, Ali R. Jazirehi, John Cohen, Cheri Milliron, Alka Kurup. Quantitative structure-activity relationships of phenolic compounds causing apoptosis. Bioorganic Medicinal Chemistry, 11(4): 617-620, 2003.
18. Cag Cal, Hermes Garban, Ali R. Jazirehi, Cindy Yeh, Yuichi Mizutani, Benjamin Bonavida. Resveratrol and cancer: chemoprevention, apoptosis, and chemoimmuno-sensitizing activities. Current Medicinal Chemistry-Anti-Cancer Agents, 3: 77-93, 2003.
19. Christos Emmanouilides, Ali R. Jazirehi, Benjamin Bonavida. Rituximab-mediated sensitization of Non-Hodgkin’s Lymphoma (NHL) B-Cells to cytotoxicity induced by Paclitaxel, Gemcitabine and Vinorelbine. Cancer Biotherapy and Radiopharmaceuticals, 17 (6): 621-630, 2003.
20. Corwin Hansch, Ali R. Jazirehi, Suresh Babu Mekapati, Rajni Garg, Benjamin Bonavida. QSAR of apoptosis induction in various cancer cells. Bioorganic Medicinal Chemsitry, 11: 3015-3019, 2003.
21. Ali R. Jazirehi, Chuen-Pei Ng, Xiao-Hu Gan, Gary Schiller, Benjamin Bonavida. Doxorubicin sensitizes the ADR-resistant 8226/Dox40 human multiple myeloma tumor cell lines to TRAIL-mediated apoptosis. Clinical Cancer Research, 7: 3874-3883, 2001.
22. Benjamin Bonavida, Chuen-Pei Ng, Ali R. Jazirehi, Gary Schiller, Yoichi Mizutani. Selectivity of TRAIL-mediated apoptosis of cancer cells and synergy with drugs: The non-toxic cancer therapeutics (Review). International J. Oncology, 15: 793-802, 1999.
Memberships in Scholarly or Professional Societies
- American Association of Bioanalysts
- American Association for Cancer Research
- American Society of Hematology
- American Association of Immunologists
- California Department of Health Services, Laboratory Field Services
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