Autophagy as a therapeutic target to enhance chemotherapy in oral squamous cell carcinoma

Abstract

Oral cancer is the 15th most common cancer worldwide and oral squamous cell carcinoma accounts for 90% of oral cancer cases. Current therapeutic interventions for OSCC include surgical intervention with radiation therapy and chemotherapy used as adjuvant therapies. Chemotherapeutic intervention alone, is often avoided due to its association with chemoresistance. This study focuses on the optimisation of chemotherapeutic interventions to reduce resistance in improve and the patients quality of life after treatment. IC50 values for Cisplatin, Carboplatin, 5-fluorouracil and docetaxel were determined in, Ca9-22, SCC4, TR146 and DOK cell lines, data that is not readily available in research papers. The induction of autophagy by chemotherapeutic intervention was also verified in these OSCC cell lines. Inhibition of cisplatin-mediated autophagy by autophagy inhibitor, chloroquine, lowered the IC50 of cisplatin OSCC cell lines in a cell type dependant manner. This increase in cisplatin-mediated cell death was shown to be linked to mitochondrial dysfunction via alterations to basal oxygen consumption rate and spare respiratory capacity. By knocking down P53 in TR146 cells, it was shown that P53- have a lower rate of basal respiration than P53+ cells. The data presented in this thesis verify the hypothesis that inhibition of autophagy can prevent cell survival mechanisms and increase the efficacy of chemotherapeutic intervention.