Nanotherapeutics induced redox resetting of oxidative and nitrosative stress: targeting glutathione-depletion in cancer

Cancer cells display a distinctive defense mechanism against any exogenous moieties that renders all treatments inefficient. Glutathione, a thiol tripeptide plays a paradoxical role in cancer as intracellular glutathione (GSH) are voracious scavengers of free radicals produced by chemotherapy, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Cancer cells show Warburg effect, wherein the intracellular GSH levels are exceptionally enhanced to overcome the oxidative stress created by ROS/RNS production or by the other free radicals generated as side products of intracellular redox reactions. Therefore, redox resetting is essential to maintain the redox homeostasis for cell survival and their proliferation and trigger escalation of GSH levels. Nanotherapeutics have facilitated the targeted delivery of GSH-depleting agents in combination with radiotherapy, chemotherapy, and novel therapeutic interventions including chemodynamic therapy (CDT), photodynamic therapy (PDT), ferroptosis induction, sonodynamic therapy (SDT), and immunotherapy are being explored. This review aims to compile the strategic role of GSH in cancer cells, the importance of nanotherapeutics for GSH depletion in cancer to target numerous forms of programmed cell death (PCD), including apoptosis, ferroptosis, necroptosis, and autophagy.