David A. Gewirtz, Ph.D.

Professor

David A. Gewirtz, Ph.D.

Department: Department of Pharmacology and Toxicology

Phone: (804) 828-9523

Fax: (804) 827-1134

Email: david.gewirtz@vcuhealth.org

Address/Location:
Massey Cancer Center
401 College Street
Goodwin Research Laboratories, Room 321
Box 980035
Richmond,

Education

  • City University of New York, Mt. Sinai, 1977.

Research interests

  • Biochemical and molecular effects of antitumor drugs and radiation in breast tumor cells and lung cancer cells.
  • Regulation of senescence arrest.
  • Involvement of autophagy in sensitivity and resistance to chemotherapy and radiation.

Senescence and Tumor Dormancy
Breast tumor cells and non-small cell lung cancer cells fail to undergo apoptotic cell death in response to either radiation or antitumor drugs such as Adriamycin and etoposide, instead demonstrating a prolonged growth arrest (Fornari et al, 1996; Watson et al, 1997). This is also the case for prostate tumor cells under conditions of androgen deprivation (Carpenter et al, 2021, 2024). Consequently, tumor cells that remain dormant for an extended time period may ultimately recover, 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 breast and lung tumor cells to radiation and chemotherapy and (ii) prevent recovery of proliferative function. We have demonstrated senolytic action in multiple experimental models (Carpenter et al, 2021, 2024; Ahmadinajad et al.2022 ; Saleh et al. 2019, 2020) Similar studies are ongoing in models of castration resistant prostate cancer. 

Regulation of senescence arrest
Our studies suggests that prolonged growth arrest in p53 wild-type cells exposed to either adriamycin or radiation reflects replicative senescence (induction of p53 and p21, and expression of the senescence marker, beta-galactosidase); 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 continuing to investigate 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).

Involvement of autophagy in sensitivity and resistance to chemotherapy and radiation.
Tumor cells that undergo senescence almost invariably also undergo autophagy, a cell “self-digestion” pathway that generates energy and metabolic intermediates under conditions of nutrient deprivation or other forms of exogenous or endogenous stress (Gewirtz et al, 2018, 2020). Ongoing studies are designed to determine to what extent autophagy facilitates senescence as well as escape from senescence in cells exposed to chemotherapy, radiation or androgen deprivation (in the case of prostate tumor cells).

Selected publications

  1. Carpenter, V, Saleh, T, Chakraborty, E, Lee, SM, Murray, G, Reed, J, Souers, A, Faber, AC, Harada, H, and Gewirtz, DA (2024) Androgen deprivation-induced senescence confers sensitivity to a senolytic strategy in prostate cancer. Biochemical Pharmacology, 226, p.116385. PMID: 38909784.
  2. Carpenter, V, Saleh, T, Lee, SM, Murray, G, Reed, J, Souers, A, Faber, AC, Harada, H and Gewirtz, DA, (2021) Androgen-deprivation induced senescence in prostate cancer cells is permissive for the development of castration-resistance but susceptible to senolytic therapy. Biochemical Pharmacology, 193, p.114765. PMID: 34536356
  3. Patel, NH, Xu, J, Saleh, T, Wu, Y, Lima, S, Gewirtz, DA. (2020) Influence of nonprotective autophagy and the autophagic switch on sensitivity to cisplatin in non-small cell lung cancer cells. Biochem Pharmacol. 175:113896. PMID: 32135156.
  4. Gewirtz, DA. The switch between protective and nonprotective autophagy; implications for autophagy inhibition as a therapeutic strategy in cancer. (2020) Biology (Basel). 9(1):12. PMID: 31947952.
  5. Patel, NH, Xu, J, Saleh, T, Wu, Y, Lima, S, Gewirtz, DA. (2020) Influence of nonprotective autophagy and the autophagic switch on sensitivity to cisplatin in non-small cell lung cancer cells. Biochem Pharmacol. 175:113896. PMID: 32135156.
  6. Saleh, T, Carpenter, VJ, Tyutyunyk-Massey, L, Murray, G, Leverson, JD, Souers, AJ, Alotaibi, MR, Faber, AC, Reed, J, Harada, H, Gewirtz, DA. (2020) Clearance of therapy-induced senescent tumor cells by the senolytic abt-263 via interference with bcl-xl -bax interaction. Mol Oncol. 14(10):2504-2519. PMID: 32652830. PMCID PMC7530780. 
  7. Patel, NH., Sohal, SS, Manjili, MH, Harrell, JC, Gewirtz, DA. (2020) The roles of autophagy and senescence in the tumor cell response to radiation. Radiat Res. 94(2):103-115. PMID: 32845995. PMCID PMC7482104. 
  8. Saleh, T, Tyutyunyk-Massey, L, Murray, GF, Alotaibi, MR, Kawale, AS, Elsayed ,Z, Henderson, SC, Yakovlev, V, Elmore, LW, Toor, A, Harada, H, Reed, J, Landry, JW, Gewirtz, DA. (2019) Tumor cell escape from therapy-induced senescence. Biochem Pharmacol. 162:202-212. PMID: 30576620.
  9. Gewirtz, DA, Tyutyunyk-Massey, L, Landry, JW. (2018) The potentially conflicting cell autonomous and cell non-autonomous functions of autophagy in mediating tumor response to cancer therapy. Biochem Pharmacol. 153:46-50. PMID: 29408462.
  10. Xu, J, Patel, NH, Saleh, T, Cudjoe Jr, EK, Alotaibi, M, Wu, Y, Lima, S, Hawkridge, AM, Gewirtz, DA. (2018) Differential radiation sensitivity in p53 wild-type and p53-deficient tumor cells associated with senescence but not apoptosis or (nonprotective) autophagy. Radiat Res. 190(5):538-557. PMID: 30132722.
  11. Elmore, LW, Di, X, Dumur, C, Holt, SE, and Gewirtz, DA. (2005). Evasion of a single-step, chemotherapy-induced senescence in breast cancer cells: implications for treatment response. Clinical Cancer Research, 11(7), pp.2637-2643. PMID: 15814644.
  12. Jones, KR, Elmore, LW, Jackson-Cook, C, Demasters, G, Povirk, LF, Holt, SE, Gewirtz, DA. (2005) p53-Dependent accelerated senescence induced by ionizing radiation in breast tumour cells. International Journal of Radiation Biology, 81(6), pp.445-458. PMID: 16308915.
  13. Elmore, LW, Rehder, CW, Di, X, McChesney, PA, Jackson-Cook, CK, Gewirtz, DA, and Holt, SE. (2002). Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction. Journal of Biological Chemistry, 277(38), pp.35509-35515. PMID:12101184.
  14. Watson, NC, Di, Y-M, Orr, MS, Fornari Jr, FA, Randolph, JK, Magnet, KJ, Jain, PT, Gewirtz, DA. (1997). Influence of ionizing radiation on proliferation, c-myc expression and the induction of apoptotic cell death in two breast tumour cell lines differing in p53 status. International Journal of Radiation Biology, 72(5), pp.547-559. PMID: 9374435.
  15. Fornari Jr, FA, Jarvis, WD, Grant, S. Orr, MS, Randolph, JK, White, FK, Gewirtz, DA. (1996) Growth arrest and non-apoptotic cell death associated with the suppression of c-myc expression in MCF-7 breast tumor cells following acute exposure to doxorubicin. Biochemical Pharmacology, 51(7), pp.931-940. PMID: 8651943.

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