Date of Award

2018

Document Type

Open Access Dissertation

Department

Biological Sciences

Sub-Department

College of Arts and Sciences

First Advisor

Minsub Shim

Abstract

The survivors of childhood cancers are often associated with adverse late effects including hypoplasia, fatigue, and infertility, which are characteristics of aging. However, the underlying mechanisms of the late effects of chemotherapy are still elusive. We have found that transgenic cyclooxygenase-2 (COX2) expression causes premature aging phenotypes. Since COX2 expression is highly induced by various chemotherapeutic agents, we further investigated the possible link between COX2 and the late effects of chemotherapy. Treatment of juvenile wild-type mice with doxorubicin (DOX), an anthracycline-based chemotherapeutic agent, resulted in premature aging phenotypes and escalated cellular senescence level in various tissues. We found that tissue expression of COX2 persists even 11 weeks after cessation of DOX treatment. Moreover, COX inhibitors successfully alleviated cellular senescence level and early aging phenotypes in DOX-treated mice. In addition, genetic deletion or pharmacological inhibition of COX2 in cell lines significantly decreased DOX-induced cellular senescence. Also, treatment with COX inhibitors induced cell death among senescent cells, possibly through inhibition of p70 and Bcl signaling, consistent with our in vivo observation. Our results indicate that chemotherapy-induced COX2 may play an important role in the late effects of chemotherapy. COX inhibitors, which have been used in medical treatments for centuries, could serve as senolytic drugs by eliminating senescent cells to restore homeostasis and rescue aging phenotypes

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