Grape seed proanthocyanidin extract ameliorates cisplatin-induced testicular apoptosis via PI3K/Akt/mTOR and endoplasmic reticulum stress pathways in rats

Xuhong Chang; Minmin Tian; Qiong Zhang; Fangfang Liu; Jinxia Gao; Sheng Li; Han Liu; Xiangbo Hou; Lei Li; Chengyun Li; Yingbiao Sun

doi:10.1111/jfbc.13825

Grape seed proanthocyanidin extract ameliorates cisplatin-induced testicular apoptosis via PI3K/Akt/mTOR and endoplasmic reticulum stress pathways in rats

J Food Biochem. 2021 Jun 21:e13825. doi: 10.1111/jfbc.13825. Online ahead of print.

Authors

Xuhong Chang¹, Minmin Tian¹, Qiong Zhang¹, Fangfang Liu¹, Jinxia Gao², Sheng Li³, Han Liu¹, Xiangbo Hou¹, Lei Li¹, Chengyun Li¹, Yingbiao Sun¹

Affiliations

¹ Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China.
² Department of Occupational Diseases, Lanzhou Municipal Center for Disease Control, Lanzhou, China.
³ Department of Public Health, The First People's Hospital of Lanzhou City, Lanzhou, China.

PMID: 34152018
DOI: 10.1111/jfbc.13825

Abstract

Testicular toxicity is an adverse reaction of the effective chemotherapy drug cisplatin (CIS). Our previous study found that grape seed proanthocyanidin extract (GSPE) had a protective effect on CIS-induced testicular toxicity. However, the protective mechanism of GSPE against CIS-induced testicular toxicity remains unknown. In this study, we aimed to investigate whether GSPE can reduce CIS-induced testicular toxicity and its potential mechanism in rats. The results showed that GSPE ameliorated CIS-induced the apoptosis of testicular cells and inhibited the protein levels of Bad, Cyt c, caspase-9, caspase-3, caspase-12, GRP78, CHOP, IRE1α, p-IRE1α, XBP-1S, PERK, p-PERK, eIF2α, and p-eIF2α. Besides, GSPE reversed the downregulation of PI3K, p-PI3K, Akt, p-Akt, mTOR, and p-mTOR protein expression induced by CIS. These results indicated that GSPE can improve CIS-induced testicular cells apoptosis via activating PI3K/Akt/mTOR and inhibiting Bad/Cyt c/caspase-9/caspase-3 pathways. And GSPE relieved endoplasmic reticulum stress-mediated apoptosis via inhibiting PREK/eIF2α and IRE1α/XBP-1S/caspase-12 pathways. In conclusion, the evidence suggested that GSPE can act as a protective agent against testicular toxicity induced by CIS. PRACTICAL APPLICATIONS: Testicular toxicity was a well-known adverse effect of cisplatin (CIS) in cancer treatment. Grape seed proanthocyanidin extract (GSPE) has been reported to serve as one of the most therapeutic potentials agents. In present study, we explored the regulatory effects of GSPE on the apoptosis induced by CIS, which involved testicular apoptosis mechanisms in rats. Our results indicated that CIS caused testicular toxicity via PI3K/AKT/mTOR and ERS mediated apoptosis pathway in rats. This toxicity was attenuated by GSPE treatment via activated PI3K/Akt/mTOR pathway, and inhibiting Bad/CytC/caspase-9/caspase-3 as well as PREK/eIF2α, IRE1α/XBP-1S/caspase-12 pathways. Our findings suggest that GSPE may be a novel protective agent against testicular toxicity induced by CIS.

Keywords: apoptosis; cisplatin; endoplasmic reticulum stress; grape seed procyanidins extract; testicular toxicity.

Abstract

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