6. Conclusions and Future PerspectivesMitochondrial redox homeostasis is an integral component of cells signaling pathways and has been shown to regulate cell transformation, survival, proliferation, invasion, angiogenesis, and metastasis. Like a double-edged sword, the roles of oxidative stress and redox state could exert beneficial or detrimental consequences in various types of cancer cells and tumor microenvironments (Figure 1). Targeting mitochondrial redox-sensitive pathways and transcriptional factors in the appropriate context offers great promise for cancer prevention and therapy, such as mitoTEPO, Auranofin and laromustine. Therefore, further study is required using animal models that critically monitor the roles of oxidative stress and redox state in the possible benefit of antioxidant. As discussed, increased mitochondrial ROS production is critical in cancer cell reprograming by inducing DNA mutations, activation of growth receptor signaling and alterations of mitochondrial genes such as Sirt3. This, however, is often coupled with upregulation of antioxidant system such as NADPH and GSH synthesis, and maintenance of reductive phenotype. This adaptive response to increased ROS production is critical not only for cancerous transformation but also important in maintenance of cancer phenotype. Moreover, this adaptive response may be largely responsible for drug resistance since cancer cells are very well known more resistant to any “oxidant” exposure compared with non-malignant cells, causing inherited problem with standard approach to kill cancer cells by oxidative stress since it leads to tremendous “off-target” non-malignant cells dysfunction and cell death. To improve the potential of translational applications of mitochondria-specific anti-tumor drugs, it is critical to monitor the specific role of oxidative stress and alterations in redox-sensitive signaling pathways in various types of cancer distinct from that is normal cells. It is also pivotal to characterize species, location and kinetics of ROS within cellular and mitochondrial compartments by new small molecule probes and genetically encoded sensors to measure ROS and thiol redox state in living cells and tissues [113,114]. Identification of Sirt3 and other critical regulators that connects mitochondrial ROS, metabolism reprogramming and cancer progression will be of significance in the future. For example, re-expression or re-activation of mitochondrial Sirt3, which is often downregulated in many cancers, may provide potential therapeutic approach. With recent advances in technology of mitochondrial research such as redox proteomics and metabonomics [115,116,117,118], interconnected mitochondrial physiology, metabolism, redox signaling in normal and cancer cells need to be uncovered to properly understand the role of mitochondrial in cancer biology.
https://www.ncbi.nlm...les/PMC4846849/
