Effect of co-treatment with doxorubicin and verapamil loaded into chitosan nanoparticles on diethylnitrosamine-induced hepatocellular carcinoma in mice.

This study aimed to investigate the potential role of co-treatment with doxorubicin (DOX) and verapamil (VRP) nanoparticles in experimentally induced hepatocellular carcinoma in mice and to investigate the possible mechanisms behind the potential favorable effect of the co-treatment. DOX and VRP were loaded into chitosan nanoparticles (CHNPs), and cytotoxicity of loaded and unloaded drugs against HepG2 cells was evaluated. Male albino mice were divided into eight groups (n = 15): (1) normal control, (2) diethylnitrosamine, (3) CHNPs, (4) free DOX, (5) CHNPs DOX, (6) free VRP, (7) CHNPs VRP, and (8) CHNPs DOX + CHNPs VRP. Either VRP or DOX loaded into CHNPs showed stronger growth inhibition of HepG2 cells than their free forms. DOX or VRP nanoparticles displayed pronounced anticancer activity in vivo through the decline of vascular endothelial growth factor and B cell lymphoma-2 contents in liver tissues, upregulation of antioxidant enzymes, and downregulation of multidrug resistance 1. Moreover, reduced cardiotoxicity was evident from decreased level of tumor necrosis factor-α and malondialdehyde in heart tissues coupled with decreased serum activity of creatine kinase-myocardial band and lactate dehydrogenase. Co-treatment with CHNPs DOX and CHNPs VRP showed superior results versus other treatments. Liver sections from the co-treatment group revealed the absence of necrosis, enhanced apoptosis, and nearly normal hepatic lobule architecture. Co-treatment with CHNPs DOX and CHNPs VRP revealed enhanced anticancer activity and decreased cardiotoxicity versus the corresponding free forms.

Protective effects of alpha-lipoic acid against benzene induced toxicity in experimental rats.

OBJECTIVE: The aim of the present study was to examine the potential protective effects of Alpha-Lipoic Acid (ALA) against benzene induced alteration in CYP2E1 gene function, DNA damage as well as the oxidant-antioxidant status. MATERIALS AND METHODS: Fifty adult male Wister rats were used for this study. Rats were randomized and divided into four groups: Group I was designated as control group and received a vehicle of olive oil; Group II was received alpha lipoic acid in a dose of (20 mg/kg, i.p.); Group III received only I.M. injection of benzene in a dose of 2 ml/kg. Group IV received both alpha lipoic acid in a dose of (20 mg/kg, i.p.) and I.M. injection of benzene in a dose of 2 ml/kg. The animals were treated on each alternate day for 30 days then all rats were sacrificed and both blood and liver tissue samples were taken to measure serum malondialdehyde (MDA) Level; serum level of reduced glutathione (GSH); level of serum 8-hydroxy-2'-deoxyguanosine; hepatic microsomal cytochrome P450 2E1 activity and gene expression. RESULTS: Benzene significantly increased serum malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and both CYP2E1 activity and gene expression but significantly decreased level of reduced glutathione (GSH). These changes are reversed upon administration of ALA. CONCLUSIONS: The current study provided evidence that the linkage between CYP2E1-dependent oxidative stress, DNA damage, and GSH homeostasis could contribute to the toxic actions of benzene which can be counteracted by ALA by its suppression action on CYP2E1, inhibition of lipid peroxidation and oxidative DNA damage as well as maintenance of intracellular antioxidants status.