Abstract
To investigate combined effect of the anticancer drug cisplatin (CP) and the opiate analgesic morphine (MOR) on liver, rats were administered MOR (10 mg/kg/day i.p. for 10 days), with or without CP (7.5 mg/kg i.p. once at day 5 of the study). MOR or CP alone caused deterioration of liver function tests and induced damage to histological architecture of liver. In addition, each drug alone caused hepatic oxidative stress, as evident by significant increase of malondialdehyde and nitric oxide, as well as the significant decrease in GSH, catalase and SOD compared to control. Administration of either MOR or CP also caused liver inflammation, evident by the increase in the pro-inflammatory cytokines; TNF-α and IL-6. In addition, either MOR or CP induced liver apoptosis, as shown by significant increase in expression of the pro-apoptotic marker; caspase 3 compared to control. Either MOR or CP also caused up-regulation of the efflux transporter P-glycoprotein (P-gp). Combining MOR with CP caused deterioration in all parameters tested compared to CP alone. Thus, treatment with MOR worsened CP-induced hepatotoxicity through oxidative stress, inflammation and apoptosis mechanisms. In addition, both drugs contributed to the up-regulation of P-gp, which might be a new mechanism for their hepatotoxic effects.
Highlights
Hepatotoxicity is one of the major side effects of cancer chemotherapy, especially when using one of the platinum-based drugs as cisplatin (CP) [1]
Enzyme-linked immunosorbent assay (ELISA) kits were purchased from Sigma-Aldrich Co
At the end of the study, total body weight of each rat was correlated with its liver weight, and the results showed that the liver index was not affected in MOR-treated group, while treatment with
Summary
Hepatotoxicity is one of the major side effects of cancer chemotherapy, especially when using one of the platinum-based drugs as cisplatin (CP) [1]. The mechanisms involved in CP-induced hepatotoxicity are not fully elucidated. Several pro-inflammatory cytokines have been shown to increase after CP treatment [3,4], suggesting a strong role of inflammation as a mechanistic process in CP-induced hepatotoxicity. Administration of CP was reported to induce hepatic programmed cell death as evident by up-regulating a number of pro-apoptotic markers [5,6]. CP might cause chemotherapy-induced neuropathic pain as a side effect [7], which may be a limiting factor for continuation of CP use as an anticancer drug. The pain might be too severe to endure without administration of strong analgesics, as opioids
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