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

Bo-yu Shen1, Chong Chen1, Yang-fan Xu1, Jia-jia Shen1, Hui-min Guo1, Hao-feng Li1, Xi-nuo Li1, Dian Kang1, Yu-hao Shao1, Zhang-pei Zhu1, Xiao-xi Yin1, Lin Xie1, Guang-ji Wang1, Yan Liang1
1 Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, China
Correspondence to: Guang-ji Wang:, Yan Liang:,
DOI: 10.1038/s41401-018-0158-8
Received: 6 June 2018
Accepted: 25 July 2018
Advance online: 14 September 2018


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.
Keywords: doxorubicin; glutathione; cardioprotection; hepatoprotection; chemotherapeutic efficacy; antioxidants

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