"Reductive stress" the overlooked side of cellular redox modulation in cancer: opportunity for design of next generation redox chemotherapeutics.

The last three decades of redox biology research have been dominated by the term "oxidative stress" since it was first coined by Helmut Sies to represent a form of cellular redox modulation characterized by redox imbalance toward overproduction of oxidants. Almost every pathological condition, including cancer, has been linked with oxidative stress and so forth; targeting oxidative stress became the strategy for the new drug discovery with anticancer drugs aiming to selectively induce oxidative stress in cancerous cells while antioxidants aiming to prevent carcinogenesis as prophylactic agents. Time has now come to realize, how harmful the other side of the cellular redox spectrum, "reductive stress," characterized by redox imbalance toward the accumulation of reducing equivalents, maybe during carcinogenesis, and to tap its potential for the design of next-generation chemotherapeutic agents. Adjuvants-causing reductive stress may also work synergistically with radiation therapy under hypoxia to achieve better tumor control. Keeping this evolving field into account, the present review provides a current understating of the role of reductive stress in carcinogenesis, the status of reductive stress-based chemotherapeutic agents with particular emphasis on sulfhydryl and selenium-containing compounds and the gap areas that need to be addressed in future.