Endogenous and induced oxidative stress in multi-cellular tumour spheroids: implications for improving tumour therapy

The endogenous oxidative stress in tumours is determined by the status of mitochondrial, metabolic, oxygen (hypoxia) and inherent enzymatic as well as non-enzymatic antioxidant defense systems, which influence tumour growth and respond to anticancer therapeutics. Induced oxidative stress is one of the important determinants of the outcome of treatment with certain chemotherapeutic drugs and ionizing radiation. The mild to moderate levels of reactive oxygen species (ROS) have often been found to trigger prosurvival responses, thereby contributing to the resistance against therapy. The higher levels of ROS stimulate multiple death pathways viz. typical and atypical apoptosis, necrosis etc, thereby enhancing the therapeutic efficiency. Therefore, approaches employing therapeutic agents that generate ROS efficiently in the tumour cells and enhance the antioxidant defense system in the normal cells could significantly enhance the therapeutic gain. Multi-cellular tumour spheroids (MCTS) offer an excellent in vitro system that mimics endogenous oxidative stress often observed in tumours, arising due to a number of factors (gradients of oxygen and nutrients, altered intercellular interaction and tumour necrosis factor), besides antioxidant defense systems similar to tumours in vivo. More importantly, MCTS resemble tumours in vivo with reference to the induced oxidative stress related responses, particularly following combinations of certain chemotherapeutic drugs and metabolic inhibitors and differs significantly from the responses in monolayer cultures. Therefore, MCTS appear to be excellent in vitro models, ideally suited for developing novel therapies that are based on the generation of oxidative stress in tumours. The present review provides a modest account on the utility of MCTS in understanding the role of oxidative stress in treatment-induced responses of tumours for designing therapies and therapeutics.