Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy

Abstract

The cellular defense system against exogenous substances makes therapeutics inefficient as intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS) or reactive nitrogen species (RNS) or other free radicals produced by the therapeutics. In the cancer cell microenvironment, the intracellular GSH level becomes exceptionally high to fight against oxidative stress created by the production of ROS/RNS or any free radicals, which are the byproducts of intracellular redox reactions or cellular respiration processes. Thus, in order to maintain redox homeostasis for survival of cancer cells and their rapid proliferation, the GSH level starts to escalate. In this circumstance, the administration of anticancer therapeutics is in vain, as the elevated GSH level reduces their potential by reduction or by scavenging the ROS/RNS they produce. Therefore, in order to augment the therapeutic potential of anticancer agents against elevated GSH condition, the GSH level must be depleted by hook or by crook. Hence, this Review aims to compile precisely the role of GSH in cancer cells, the importance of its depletion for cancer therapy and examples of anticancer activity of a few selected metal complexes which are able to trigger cancer cell death by depleting the GSH level.

Research Progress of Disulfide Bond Based Tumor Microenvironment Targeted Drug Delivery System

“…In normal tissue cells and plasma, GSH levels range from 0.5 to 10 mmol/L, while GSH concentration in tumor tissue is more than four times that of normal cells. 43 , 44 This concentration difference is an important prerequisite for targeting tumors through disulfide bonds. Studies have shown that GSH can counteract the anti-tumor effects of chemotherapy drugs by promoting tumor cell proliferation, binding to or responding to drugs, interacting with reactive oxygen species, alleviating damage to proteins or DNA, or participating in DNA repair processes.…”

“…Studies have shown that GSH can counteract the anti-tumor effects of chemotherapy drugs by promoting tumor cell proliferation, binding to or responding to drugs, interacting with reactive oxygen species, alleviating damage to proteins or DNA, or participating in DNA repair processes. 43 , 45 , 46 At the same time, some drugs, such as platinum-based chemotherapy drugs, can also induce the production of GSH, further weakening its anti-tumor ability. 47 In conclusion, the high level of GSH is a disadvantage for anti-tumor, and its consumption by disulfide bonds is more conducive to tumor inhibition.…”