Michael G. Kemp, Ph.D. (Advisor); Ravi P. Sahu, Ph.D. (Committee Member); Yong-jie Xu, M.D., Ph.D. (Committee Member)
Master of Science (MS)
Cisplatin is a DNA damage-based chemotherapeutic drug widely used to treat various types of cancers; however, the treatment's toxicity restricts its efficiency. Studies have shown that the circadian rhythm controls the DNA damage response and affects the repair pathways of cisplatin-induced DNA damage. Circadian clock modulation, therefore, has been proposed to be a potential mechanism for enhancing cisplatin tolerability. Here we used clock-enhancing molecules to evaluate the effect of pharmacological clock modulation on cisplatin cytotoxicity. Using cultured human cell lines, cisplatin cytotoxicity was found to be attenuated following treatment with circadian-enhancing molecules KS15 and SR8278. Moreover, the protein and mRNA levels of cell cycle and apoptosis regulators, as well as clock-controlled genes, were modified in response to KS15 and SR8278. Those molecules were also able to enhance cisplatin-induced DNA adducts removal and induce G1-phase cell cycle arrest. Our findings suggest that the use of circadian clock modulators has promising implications for improving cancer care and treatment outcomes
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
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