Abstract

It is widely believed that normal mammalian cells maintain a delicate balance between ROS generation and their neutralization by endogenous antioxidant systems. Transformation of normal cells to tumor cells involves imbalance of redox system which results in enhanced ROS level through oxidative stress process.  In recent years,  evidence is accumulating to show that stemness of cells is characterized by low ROS level which drives self renewal and differentiation capabilities to normal and cancer stem cells ( CSCs). It is observed that CSCs have evolved to maintain a low level of intracellular ROS as a consequence of the modulation of redox antioxidants , metabolic reprogramming and reduced DNA damage repair. Increasing evidence suggests that a low concentration of ROS is associated with maintaining the stemness of CSCs and contribute to tumorigenesis and progression. A new approach to control tumor development consists in regulation of ROS to deprive the cells from advantages of cancer progression promotion. It appears that ROS related signaling is more tightly regulated in certain unknown tiers than generally believed. Low to moderate ROS level ensure survival of normal cells, relatively increased ROS drive epithelial –mesenchymal cell transition and larger excess cytosolic ROS may trigger apoptotic signals responsible to persuade tumor cells to death and thereby overcoming their resistance to anticancer therapies,namely, chemotherapy and radiotherapy. CSCs are evolved in tumor microenvironment which is  hypoxic due to poor vasculature and accelerated glycolytic  processes resulting in the induction of hypoxia inducing factors (HIF) through interplay of cellular ROS. The underlying mechanisms in these processes remain unclear but it appears  there exist various systems for the regulation of ROS in CSCs, such as through CSC surface markers, Oct4, CD133+ etc and these help maintain the ROS at a favorable cancer cell survival pathways. Thus modulation of oxidative stress appears to be a promising approach for the preferential killing of cancer cells including CSCs. Results from our laboratory on certain flavonoids antioxidants induced ROS in radio-tumor toxicity will be described. It is argued that tight regulation of signaling pathways of ROS and their controlled modulation may help predict prognosis of chemo and radiotherapies. Cytosolic modulation of ROS may help develop a new therapeutic approach with a reduced tendency of tumor cells to follow survival route and increased index of apoptotic trigger in the target cells including CSCs to overcome resistance to anticancer therapies.