Abstract Background: Cyclophosphamide (CP) is an alkylating anticancer drug used for the treatment of various cancer and noncancer disorders. Toxicity of CP is well characterized using different test systems. However, its intestinal genotoxicity and cytotoxicity are the least explored and the mechanism is not fully investigated. Valproic acid (VPA) has been reported as a histone deacetylase (HDAC) inhibitor, which modulates the cytotoxicity of anticancer drugs. The present study aimed to investigate the influence of VPA on CP-induced genotoxicity and cytotoxicity in the colon of mice. Methods: In the 16-day experiment, animals were treated with VPA alone (500 mg/kg/day), CP alone (50 mg/kg, on the 4th, 8th, 12th, and 16th days), and the combination of CP and VPA, while in the 28-day experiment, animals were treated with VPA alone (300 mg/kg/day, 5 days/week), CP alone (100 mg/kg/week), and the combination of low and high dose of VPA (VPA150+CP and VPA300+CP). Animals were sacrificed 24 h after the administration of the last dose. The influence of VPA treatment on CP-induced genotoxicity and cytotoxicity was assessed by the evaluation of oxidative stress, DNA damage, histology, and the expression of 8-hydroxy-guanosine and phosphorylated histone H2AX by immunohistochemistry. Results and conclusions: The present study's results demonstrated that VPA treatment significantly decreased the CP-induced DNA damage, cytotoxicity, and expression of γH2AX in the colon as revealed by the comet assay and histological as well as immunohistochemical evaluation. VPA treatment significantly ameliorated the CP-induced DNA damage and cytotoxicity in the colon of mice.
Abstract Background: Cyclophosphamide (CP) is an alkylating anticancer drug used for the treatment of various cancer and noncancer disorders. Toxicity of CP is well characterized using different test systems. However, its intestinal genotoxicity and cytotoxicity are the least explored and the mechanism is not fully investigated. Valproic acid (VPA) has been reported as a histone deacetylase (HDAC) inhibitor, which modulates the cytotoxicity of anticancer drugs. The present study aimed to investigate the influence of VPA on CP-induced genotoxicity and cytotoxicity in the colon of mice. Methods: In the 16-day experiment, animals were treated with VPA alone (500 mg/kg/day), CP alone (50 mg/kg, on the 4th, 8th, 12th, and 16th days), and the combination of CP and VPA, while in the 28-day experiment, animals were treated with VPA alone (300 mg/kg/day, 5 days/week), CP alone (100 mg/kg/week), and the combination of low and high dose of VPA (VPA150+CP and VPA300+CP). Animals were sacrificed 24 h after the administration of the last dose. The influence of VPA treatment on CP-induced genotoxicity and cytotoxicity was assessed by the evaluation of oxidative stress, DNA damage, histology, and the expression of 8-hydroxy-guanosine and phosphorylated histone H2AX by immunohistochemistry. Results and conclusions: The present study's results demonstrated that VPA treatment significantly decreased the CP-induced DNA damage, cytotoxicity, and expression of γH2AX in the colon as revealed by the comet assay and histological as well as immunohistochemical evaluation. VPA treatment significantly ameliorated the CP-induced DNA damage and cytotoxicity in the colon of mice.
Authors: Elerson C Costalonga; Luiza J de Freitas; Deise da S P Aragone; Filipe M O Silva; Irene L Noronha Journal: PLoS One Date: 2017-09-05 Impact factor: 3.240