Selective induction of oxidative stress in cancer cells via novel therapeutic approaches

Cancer cells are characterised by constitutive oxidative stress due to overproduction of reactive oxygen species (ROS) as a result of metabolic rewiring and oncogenic transformation. Redox homeostasis is directly linked with metal homeostasis, in particular redox active metals. Cancer cells are reported to have higher metal uptake properties compared to normal cells to sustain their high metal requirement.The main scope of this study is to investigate different therapeutic approaches of inducing oxidative stress in cancer cells. Our primary objective has been to develop novel combination regimens that increase intracellular ROS levels to induce preferential and selective cytotoxicity against cancer cells with minimal implications to normal cells. Our secondary objective was to assess the potential for improving individual agents useful in the combination therapy approach. This resulted in the development of novel metal chelators based on structural modification of the heavily studied series of pyridyl ketone thiosemicarbazones.Consequently, the research work presented in this thesis is focused on cell based biological studies of novel combinations of agents or novel metal chelating agents targeting ROS generation and metal mobilisation in cancer cells.