Defense Date

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

David A. Gewirtz

Abstract

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that senescence is not obligatorily an irreversible process. Our observations indicate that H460 non-small cell lung cancer cells induced into senescence by exposure to etoposide, and enriched based on β-galactosidase staining and size, were shown to recover reproductive capacity, which was accompanied by resolution of the DNA-damage-response (downregulation of p53 and p21Cip1 induction), attenuation of the Senescence-associated Secretory Phenotype (SASP). To overcome the reservation that the newly dividing cells may not have been derived from the senescent population and in an effort to establish that escape from TIS is feasible, tumor cells induced into senescence by chemotherapy were enriched for senescence by flow cytometry; the subsequent division of senescent cells was demonstrable utilizing both real-time, live microscopy and High Speed Live Cell Interferometry (HSLCI). Furthermore, sorted senescent cells were observed to form tumors when implanted in immune deficient mice and with a significant delay in immunecompetent mice. As chemotherapy induced senescent cells have been identified in patient tumors, it is reasonable to propose that tumor cells that escape from senescence could contribute to disease recurrence. In addition, therapy-induced senescence could prove to reflect one form of tumor dormancy. Recently, ABT263 has been used as a senolytic drug, effectively eliminating senescent cells from aging-related animal models. Here, we utilize ABT263 in a two-hit approach to eliminate senescent tumor cells that persistent after exposure to chemotherapy. ABT263 results in the killing of senescent tumor cells in a concentration-dependent manner and shifts the response towards apoptotic cell death. Furthermore, sequential administration of ABT263 interferes with the ability of senescent tumor cells to recover growth potential. These results indicate that senescent tumor cells can contribute to cancer relapse by acquiring proliferative properties and that senolytic therapy allows for the clearance of dormant senescent tumor cells and will potentially decrease cancer recurrence rates.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

10-31-2018

Available for download on Thursday, October 31, 2019

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