Education: City University of New York, Mt. Sinai, 1977
Research interests: Biochemical and molecular effects of antitumor drugs and radiation in breast tumor cells; regulation of senescence arrest; sensitization to apoptotic and autophagic cell death; development of novel antitumor drugs.
Breast tumor cells fail to undergo apoptotic cell death in response to either radiation or the antitumor drug adriamycin, instead demonstrating a prolonged growth arrest (Fornari et al, 1996; Watson et al, 1997). Consequently, breast tumor cells that remain dormant for an extended time period may ultimately recover to repopulate the breast, leading to disease recurrence. Current research efforts are directed at the development of approaches for promoting cell death in order to (i) enhance the response of the breast tumor cell to radiation and chemotherapy and (ii) prevent recovery of proliferative function. An additional focus of the current work is to understand the factors that regulate the prolonged senescence-like arrest that occurs in response to ionizing radiation and chemotherapeutic drugs such as adriamycin.
A. Reciprocal regulation of apoptosis and senescence. Our recent work suggests that prolonged growth arrest in p53 wild-type cells exposed to either adriamycin or radiation reflects replicative senescence (induction of p53 and p21, expression of beta-galactosidase, suppression of hTERT and of telomerase); in contrast, non-senescent growth arrest in p53 mutant cells is succeeded by a wave of apoptotic cell death (Elmore et al, 2002). We are investigating both biochemical and molecular regulation of senescence arrest and the basis for recovery of proliferative function in a subpopulation of the arrested cells (Elmore et al, 2005; Jones et al, 2005).
B. Radiosensitization and chemosensitization through the promotion of autophagy. Prior exposure of p53 wild-type breast tumor cells to (relatively nontoxic) Vitamin D3 analogs is permissive for apoptosis and sensitizes cells to adriamycin and irradiation (Sundaram and Gewirtz, 1999; Sundaram et al, 2003). We are exploring the capacity of the Vitamin D3 analogs to promote autophagic cell death ( DeMasters et al, 2006) and to interfere with senescence in response to adriamycin or radiation.
C. Drug Development. In collaboration with faculty in the Departments of Medicinal Chemistry, the Dental School, the Department of Chemistry and the University of Richmond, studies are under way to develop a new class of microtubule poisons for the treatment of breast cancer (Arthur et al, 2007) as well as trans platinum compounds for the treatment of ovarian cancer ( Aris et al, 2007).
Zhang X, Haney KM, Richardson AC, Wilson E, Gewirtz DA, Ware JL, Zehner ZE, and Zhang Y. (2010) Anibamine, a natural product CCR5 antagonist, as a novel lead for the development of anti-prostate cancer agents. Bioorg Med Chem Lett. 20(15):4627-30.
Gewirtz DA, Bristol ML, and Yalowich JC. (2010) Toxicity issues in cancer drug development. Curr Opin Investig Drugs. 11(6):612-4.
Klionsky DJ, Codogno P, Cuervo AM, Deretic V, Elazar Z, Fueyo-Margareto J, Gewirtz DA, Kroemer G, Levine B, Mizushima N, Rubinsztein DC, Thumm M, and Tooze SA. (2010) A comprehensive glossary of autophagy-related molecules and processes. Autophagy. 6(4):438-448.
Di X, Gennings C, Bear HD, Graham LJ, Sheth CM, White KL Jr, and Gewirtz DA. (2010) Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res Treat. 124(2):349-60.
Gewirtz DA. (2009) Autophagy, senescence and tumor dormancy in cancer therapy. Autophagy. 5(8):1232-4.
Dalyot-Herman N, Delgado-Lopez F, Gewirtz DA, Gupton JT, and Schwartz EL. (2010) Interference with endothelial cell function by JG-03-14, an agent that binds to the colchicine site on microtubules. Biochem Pharmacol. 78(9):1167-77.
Gewirtz DA, Hilliker ML, and Wilson EN. (2009) Promotion of autophagy as a mechanism for radiation sensitization of breast tumor cells. Radiother Oncol. 92(3):323-8.
Di X, Shiu RP, Newsham IF, and Gewirtz DA. (2009) Apoptosis, autophagy, accelerated senescence and reactive oxygen in the response of human breast tumor cells to adriamycin. Biochem Pharmacol. 2009 Apr 1;77(7):1139-50.