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Is the combinational administration of doxorubicin and glutathione a reasonable proposal?
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-09-14 , DOI: 10.1038/s41401-018-0158-8 Bo-Yu Shen 1 , Chong Chen 1 , Yang-Fan Xu 1 , Jia-Jia Shen 1 , Hui-Min Guo 1 , Hao-Feng Li 1 , Xi-Nuo Li 1 , Dian Kang 1 , Yu-Hao Shao 1 , Zhang-Pei Zhu 1 , Xiao-Xi Yin 1 , Lin Xie 1 , Guang-Ji Wang 1 , Yan Liang 1
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-09-14 , DOI: 10.1038/s41401-018-0158-8 Bo-Yu Shen 1 , Chong Chen 1 , Yang-Fan Xu 1 , Jia-Jia Shen 1 , Hui-Min Guo 1 , Hao-Feng Li 1 , Xi-Nuo Li 1 , Dian Kang 1 , Yu-Hao Shao 1 , Zhang-Pei Zhu 1 , Xiao-Xi Yin 1 , Lin Xie 1 , Guang-Ji Wang 1 , Yan Liang 1
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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.
中文翻译：
阿霉素和谷胱甘肽联合用药是否合理？
在常规癌症治疗过程中联合使用抗氧化剂和化疗药物是肿瘤学中最具争议的领域之一。尽管阿霉素（DOX）和谷胱甘肽（GSH）药物联合使用的数据已经探索了20多年，但其持续时间、给药途径和真实合理性尚未完全了解。在目前的研究中，我们系统地研究了体内和体外模型的药代动力学 (PK) 和药效学 (PD)，以阐明 GSH 对 DOX 毒性和功效的影响。我们首先研究了 GSH 在 Balb/c 小鼠、H9c2 和 HL7702 细胞中的心脏保护和肝脏保护作用。我们表明，外源性 GSH（每天 5、50 和 500 mg/kg，胃内）通过增加细胞内 GSH 水平显着减弱 DOX 诱导的心脏毒性和肝毒性，而升高的 GSH 浓度不影响 DOX 在小鼠心脏和肝脏中的暴露。从PK和PD的角度，然后在异种移植裸鼠和癌细胞模型，包括MCF-7，HepG2和Caco-2细胞中研究了GSH对DOX化疗功效的影响，这表明给予外源性GSH剂量-尽管升高的 GSH 水平既不影响体内肿瘤中 DOX 的浓度，也不影响体外 MCF-7 肿瘤细胞中 DOX 的摄取，但在体内和体外依赖性地减弱了 DOX 的抗癌功效。
更新日期：2019-01-26
中文翻译：
阿霉素和谷胱甘肽联合用药是否合理？
在常规癌症治疗过程中联合使用抗氧化剂和化疗药物是肿瘤学中最具争议的领域之一。尽管阿霉素（DOX）和谷胱甘肽（GSH）药物联合使用的数据已经探索了20多年，但其持续时间、给药途径和真实合理性尚未完全了解。在目前的研究中，我们系统地研究了体内和体外模型的药代动力学 (PK) 和药效学 (PD)，以阐明 GSH 对 DOX 毒性和功效的影响。我们首先研究了 GSH 在 Balb/c 小鼠、H9c2 和 HL7702 细胞中的心脏保护和肝脏保护作用。我们表明，外源性 GSH（每天 5、50 和 500 mg/kg，胃内）通过增加细胞内 GSH 水平显着减弱 DOX 诱导的心脏毒性和肝毒性，而升高的 GSH 浓度不影响 DOX 在小鼠心脏和肝脏中的暴露。从PK和PD的角度，然后在异种移植裸鼠和癌细胞模型，包括MCF-7，HepG2和Caco-2细胞中研究了GSH对DOX化疗功效的影响，这表明给予外源性GSH剂量-尽管升高的 GSH 水平既不影响体内肿瘤中 DOX 的浓度，也不影响体外 MCF-7 肿瘤细胞中 DOX 的摄取，但在体内和体外依赖性地减弱了 DOX 的抗癌功效。
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