EVALUATING THE CHEMOTHERAPEUTIC EFFECTS OF SR9009 AND ESOMEPRAZOLE ON ORAL SQUAMOUS CELL CARCINOMA USING CIRCADIAN-TAILORED INNOVATIVE THERAPEUTIC APPROACHES
Harri shivanantham, Aparna
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The vast majority (95%) of oral cancer, which has an overall 5-year survival rate of 66%, is oral squamous cell carcinoma (OSCC). New potential triggers, including circadian clock disruption that is caused by multiple lifestyle traits such as chronic gastroesophageal reflux and human papillomavirus (HPV) infection are emerging new causal factors that might be responsible for higher population incidence of OSCC among young people and females in particular as well as for unpredictable disease outcomes. Despite promising advancements in chemotherapy, there are several limitations. Hence, there is a need for new personalized therapeutic approaches. Evidence indicates designing a rhythmic drug release according to circadian time and/or resetting disrupted circadian rhythms could minimize chemotherapeutics drug-related toxicities and enhance treatment efficiency in OSCC. Furthermore, our lab has previously shown that antacid medication may have significant therapeutic benefits in head and neck SCC. In this study, we aim to evaluate the chemotherapeutic effects of SR9009, a circadian clock regulating drug, and/or Esomeprazole, a proton pump inhibitor in HPV- (FaDu) and HPV+ (2A3) OSCC cell lines. To study the extent of disruption of circadian clock gene expression levels after Esomeprazole administration, we analysed the expression of clock genes, BMAL1 and REV-ERBα by Immunohistochemistry, Immunofluorescence, and RT-qPCR in the tumor samples of these cell lines inoculated in mice to generate OSCC in vivo. Chemotherapeutic effects of SR9009 and Esomeprazole were determined in vitro using these same OSCC cell lines by cell viability, cell proliferation, and cell migration assays. Circadian rhythms in the cells were synchronized by Forskolin prior to each of the undertaken analyses. Gene expression profiles were evaluated at 24, 30, 36, 42, and 48h after drug administration to identify the optimal time-of-day for drug delivery and to characterize core clock gene expression changes. The results showed significant differences in the expression of BMAL1 and REV-ERBα in tumors generated upon inoculation of Eso-treated OSCC cell lines compared to tumors generated upon no treated OSCC cell lines. These data suggest different mechanisms of action between HPV+ and HPV- OSCC. The treatment of SR9009 and Esomeprazole alone and in combination inhibited cell viability, cell proliferation, and cell migration in both cell lines. This drug combination demonstrated strong synergistic effects resulting in the circadian oscillation of gene expression levels for 24h-cycles after drug administration. These findings suggest that the circadian clock and drug treatment are inextricably linked to OSCC outcomes. However, additional research is needed to test these drugs in pre-clinical animal models and to find the optimal time of drug delivery, corresponding to the expression of circadian core clock genes, optimized anti-cancer effects, and the minimum toxicity possible for improved OSCC outcomes.
DegreeMaster of Science (M.Sc.)
DepartmentPharmacy and Nutrition
CommitteeDobson, Roy; Papagerakis, Silvana; Wasan, Ellen; Mousseau, Darrell
Oral squamous cell carcinoma, circadian rhythm, SR9009, Esomeprazole, chronotherapy