Is the combinational administration of doxorubicin and glutathione a reasonable proposal?

Abstract

The combinational administration of antioxidants and chemotherapeutic agents during conventional cancer treatment is among one of the most controversial areas in oncology. Although the data on the combinational usage of doxorubicin (DOX) and glutathione (GSH) agents have been explored for over 20 years, the duration, administration route, and authentic rationality have not yet been fully understood yet. In the current study, we systematically investigated the pharmacokinetics (PK) and pharmacodynamics (PD) with both in vivo and in vitro models to elucidate the influence of GSH on the toxicity and efficacy of DOX. We first studied the cardioprotective and hepatoprotective effects of GSH in Balb/c mice, H9c2, and HL7702 cells. We showed that coadministration of exogenous GSH (5, 50, and 500 mg/kg per day, intragastric) significantly attenuated DOX-induced cardiotoxicity and hepatotoxicity by increasing intracellular GSH levels, whereas the elevated GSH concentrations did not affect the exposure of DOX in mouse heart and liver. From PK and PD perspectives, then the influences of GSH on the chemotherapeutic efficacy of DOX were investigated in xenografted nude mice and cancer cell models, including MCF-7, HepG2, and Caco-2 cells, which revealed that administration of exogenous GSH dose-dependently attenuated the anticancer efficacy of DOX in vivo and in vitro, although the elevated GSH levels neither influenced the concentration of DOX in tumors in vivo, nor the uptake of DOX in MCF-7 tumor cells in vitro. Based on the results we suggest that the combined administration of GSH and DOX should be contraindicated during chemotherapy unless DOX has caused serious hepatotoxicity and cardiotoxicity.

Hydrogen Gas in Cancer Treatment

“…Doxorubicin, an anthracycline antibiotic, is an effective anticancer agent in the treatment of various cancers, but its application is limited for the fatal dilated cardiomyopathy and hepatotoxicity (81, 82). One in vivo study showed that intraperitoneal injection of hydrogen-rich saline ameliorated the mortality, and cardiac dysfunction caused by doxorubicin.…”

Polyphenol-Based Nanoscale Iron Exchangers for Regulating Anticancer Chemotherapy by Modulating the Activity of Intracellular Glutathione

“…The elevated intracellular levels of GSH, its strong correlation with resistance to anticancer drugs, and their reduced efficacy provide means to develop effective tools to treat cancer following glutathione modulation. , Additionally, oxidative stress due to high doses of a conventional chemotherapy drug, e.g., doxorubicin (Dox), poses a detrimental impact on patient health. Therefore, a strategy involving GSH modulation toward improving the therapeutic index of chemodrugs is highly desirable.…”

“…In several disease conditions, increased glutathione synthesis is reported, which is probably utilized by the cells to counter the increased reactive oxygen species (ROS) levels, like in several cancer types. , GSH is the reduced form of glutathione disulfide (GSSG), which acts on xenobiotics, including anticancer drugs such as cisplatin, and is known to make them ineffective . It is also known that increasing GSH levels lower the efficacy of chemotherapeutic drugs like doxorubicin, which is an anthracycline class of drug. Doxorubicin is known to bind to DNA-associated enzymes such as DNA topoisomerase II, cause histone eviction, intercalate with DNA base pairs, and target multiple molecular targets such as AMPK, producing cytotoxic effects …”

“…8 GSH is a cofactor of the multidrug resistance protein (MRP) family of membrane transport proteins involved in pumping out many chemotherapeutic drugs such as doxorubicin. 5 Studies have also shown that depleting GSH through biosynthesis inhibitors such as L-buthionine (S,R)-sulfoximine (BSO) prevents the export of drugs from previously multidrugresistant cells. It thus sensitized the cancer cells against several drugs such as daunorubicin, doxorubicin, vincristine, and VP-16.…”

Mitochondrial Dysfunction Pathway Alterations Offer Potential Biomarkers and Therapeutic Targets for Ovarian Cancer

“…Generally, ROS is regarded as a double-edged sword since low levels of ROS can promote tumor cell proliferation, infiltration, metastasis, and chemoradiotherapy resistance [ 90 ], whereas excessive levels of ROS over the cytotoxic threshold induce oxidative stress, cause oxidative damage, and initiate apoptotic signaling in cancer cells [ 91 ]. Therefore, some anticancer agents can specifically target cancer cells by causing an excessive accumulation of ROS and stimulating ROS-dependent cell death pathways [ 92 ].…”