Induction of heme oxygenase-1 with hemin alleviates cisplatin-induced reproductive toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line.
Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt.
Gehan Hussein
GH
Heeba
Hormone Evaluation Department, National Organization for Drug Control and Research, NODCAR, 6 Abu Hazem St., Pyramids, Giza, Egypt. Electronic address: alaa17mm@gmail.com.
Alaaeldin Ahmed
AA
Hamza
Department of Biochemistry, Faculty of Pharmacy, MTI University, Cairo, Egypt.
Soha Osama
SO
Hassanin
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006427:Hemin / Q000494:pharmacology*; D007248:Infertility, Male / Q000139:chemically induced* / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats
D000970:Antineoplastic Agents; D018836:Inflammation Mediators; D020011:Protective Agents; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D006427:Hemin; D051547:Heme Oxygenase-1; D002945:Cisplatin
Cisplatin; Heme-oxygenase-1; Male rats; Reproductive toxicity; Zinc protoporphyrin