Modulating mitochondrial metabolism to kill cancer cells

Cancer is the second leading cause of mortality and morbidity worldwide, with over 9 million deaths documented per year. Osteosarcoma is an aggressive and malignant bone tumour fatal in both children and adults. Cancer cells exhibit relatively high levels of ROS consequently from the metabolic activity needed to aid their excessive growth requirements. To compensate and maintain homeostasis, cancer cells have a strong dependency on antioxidant systems to scavenge and disrupt this increased production of ROS. This dependency provides a potential vulnerability, as influencing these cells to increase ROS generation above antioxidant capabilities could push ROS levels above a toxic threshold triggering the initiation of cell death.

In this thesis, the effects of curcumin and pioglitazone were examined to determine if they stimulate mitochondrial biogenesis to increase reactive oxygen species and oxidative stress to kill 143B osteosarcoma cells. Treatment with curcumin alone, or curcumin combined with pioglitazone, reduced 143B osteosarcoma cell proliferation after 8 days, while effects on mtDNA copy number per cell were unaffected, suggesting mitochondrial biogenesis was not stimulated. Interestingly, steady state levels of mitochondrial complex IV were significantly decreased, suggesting mitochondrial function is instead downregulated. ROS production was significantly increased by curcumin or pioglitazone treatment alone, however combined treatment with curcumin and pioglitazone had no effect on ROS production.

Overall, these findings highlight that curcumin and pioglitazone can alter mitochondrial oxidative phosphorylation and/or ROS production in 143B osteosarcoma cells. Moreover, curcumin, or curcumin combined with pioglitazone, can supress osteosarcoma cell growth and can be explored as a potential avenue for cancer treatment.