Abstract
Puerarin was a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen). In present study effect of puerarin on cisplatin nephrotoxicity was evaluated. Rat model of nephrotoxicity was established by a single intraperitoneal injection of cisplatin (7mg/kg). Puerarin was administrated through caudal vein injection once per day at the dose of 10mg/kg, 30mg/kg and 50mg/kg. Biochemical assays showed that after cisplatin treatment the serum urea and creatinine increased significantly compared with control (P<0.05). Cisplatin treatment significantly increased xanthine oxidase (XO) activity and malondialdehyde (MDA) formation, and significantly decreased the levels and /or activities of enzymatic and non-enzymatic antioxidants (GSH, GPx, GST, GR, SOD, CAT), in the kidney tissues. Renal levels of TNF-α and IL-6, two important inflammatory cytokines, were also upregulated by cisplatin. Histopathological examination indicated that cisplatin treatment resulted in severe necrosis and degeneration, hyaline casts in the tubules, intertubular hemorrhage, congestion and swelling in glomerulus and leukocytes infiltration in the kidney tissues. Western blot results demonstrated that cisplatin increased TLR4 and NF-κB protein expression in the kidney tissues. However, all these changes induced by cisplatin were significantly attenuated by puerarin treatment in dose-dependent manner, which indicated the renal protective effect of puerarin. Cell culture experiments illustrated that puerarin alone treatment concentration-dependently inhibited COLO205 and HeLa tumor cell growth and dose-dependently promoted the antitumor activity of cisplatin in COLO205 and HeLa tumor cells. The promotion effects might be attributed to suppression of cisplatin-increased NF-κB p65 expression by puerarin. Taken together, findings in this study suggested that puerarin exhibited renal protection against cisplatin nephrotoxicity via inhibiting TLR4/NF-κB signaling, with no inhibition but promotion effect on the antitumor activity of cisplatin. Puerarin might be a promising adjuvant agent for cisplatin chemotherapy.
Highlights
As one of most potent anti-tumor drugs, cisplatin was used for treatment of a wide variety of solid tumors including testicular, ovarian, bladder, endometrial, cervical, and lung cancers [1,2,3,4,5]
The results showed that cisplatin-induced significant increases in serum urea and creatinine, lipid peroxidation (MDA level), oxidant (XO), inflammation mediators (TNF-α, IL-6) and significant decreases in some enzymatic and non-enzymatic antioxidants (GSH, glutathione peroxidase (GPx), GST, glutathione reductase (GR), superoxide dismutase (SOD), CAT) in kidney tissues were dose-dependently inhibited by puerarin treatment, which indicated the renal protective effects of puerarin
Western blot analyses demonstrated that cisplatin-increased Toll-like receptor 4 (TLR4) and NF-κB p65 proteins expression in kidney tissues were reduced by puerarin in concentration-dependent manner, which indicated that it was via inhibiting TLR4/NF-κB pathway puerarin exerted renal protection
Summary
As one of most potent anti-tumor drugs, cisplatin was used for treatment of a wide variety of solid tumors including testicular, ovarian, bladder, endometrial, cervical, and lung cancers [1,2,3,4,5]. Owing to the fact that cisplatin exerted potent antitumor activity and couldn’t be abandoned at present in clinic, an urgent demand existed for cancer researchers to develop new adjuvant therapy to ameliorate toxicities of cisplatin without inhibitory effects on the antitumor activity of cisplatin. Phytochemicals attracted more and more eyeballs of cancer scientists [7, 8] and some herbal compounds have been studied to attenuate cisplatin nephrotoxicity [6, 9,10,11,12], which might potentially help to expand the clinical application of cisplatin. The present study was aimed to answer this question, which would help to justify the future clinical application of puerarin in cancer treatment in combination with cisplatin as adjuvant therapy to reduce toxicities. The molecular mechanisms of puerarin action were investigated in this study
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