Roflumilast protects from cisplatin-induced testicular toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line. Role of NF-κB-p65, cAMP/PKA and Nrf2/HO-1, NQO1 signaling

被引:31
作者
Abdel-Wahab, Basel A. [1 ,2 ]
Walbi, Ismail A. [3 ]
Albarqi, Hassan A. [4 ]
Ali, Fares E. M. [5 ]
Hassanein, Emad H. M. [5 ]
机构
[1] Najran Univ, Coll Pharm, Dept Pharmacol, Najran, Saudi Arabia
[2] Assiut Univ, Coll Med, Dept Med Pharmacol, Assiut, Egypt
[3] Najran Univ, Coll Pharm, Dept Clin Pharm, Najran, Saudi Arabia
[4] Najran Univ, Coll Pharm, Dept Pharmaceut, Najran, Saudi Arabia
[5] Al Azhar Univ, Fac Pharm, Dept Pharmacol & Toxicol, Assiut, Egypt
关键词
Cisplatin; Testicular toxicity; Phosphodiesterase-4; inhibitors; Roflumilast; Nrf2/HO-1; NF-kappa beta; NF-KAPPA-B; INDUCED REPRODUCTIVE TOXICITY; ELEMENT-BINDING PROTEIN; OXIDATIVE STRESS; PHOSPHODIESTERASE-4; INHIBITOR; HEME OXYGENASE-1; DNA-DAMAGE; APOPTOSIS; PATHWAY; INFLAMMATION;
D O I
10.1016/j.fct.2021.112133
中图分类号
TS2 [食品工业];
学科分类号
0832 ;
摘要
Cisplatin (CIS)-induced testicular injury is a major obstacle in its application as antineoplastic agent. In this study, we investigated the protective effect and mechanism of roflumilast (ROF), a PDE4 inhibitor, against CIS-induced testicular toxicity in rats. Besides, the cytotoxic effect of CIS, with and without ROF, was evaluated on PC3 cell line. ROF reversed CIS-induced abnormalities in sperm characteristics, normalized serum testosterone level, and ameliorated CIS-induced alterations in testicular and epidydimal weights and restored normal testicular structure. Moreover, ROF increased intracellular cAMP level, PKA and HO-1 activities and Nrf2, NQO-1 and HO-1 gene expression, improved testicular oxidative stress parameters (TBARS, NO, GSH levels, and CAT activity) and inflammatory mediators (IL-1 beta and TNF-alpha, and NF-kappa beta p65gene expression) and reduced the proapoptotic proteins, caspase-3, Bax and increased Bcl-2. Lastly, in vitro analyses showed that ROF augmented the anticancer efficacy of CIS and enhanced the increase in gene expression of Nrf2, HO-1, and NQO-1 and the inhibition of gene expression of NF-kappa beta p65 induced by CIS and enhanced its apoptotic effect in PC3 cells. Conclusively, PDE4 inhibition with induction of Nrf2/HO-1, NQO-1 is a potential therapeutic approach to protect male reproductive system from the detrimental effects with augmenting, the antineoplastic effect of CIS.
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页数:15
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