Combinatorial Effects of Thymoquinone on the Anticancer Activity and Hepatotoxicity of the Prodrug CB 1954

Background: One of the major causes of clinical trial termination is the liver toxicity induced by chemotherapeutic agents. Treatment with anticancer drugs like CB 1954 (5-(Aziridin-1-yl)-2,4-dinitrobenzamide) is associated with significant hepatotoxicity. Thymoquinone (TQ), extracted from Nigella sativa, is reported to possess anticancer and hepatoprotective effects. The aims of the present study were to use TQ to reduce hepatotoxicity associated with CB 1954 and to augment its anticancer activity against the resistant mouse mammary gland cell line (66 cl-4-GFP). Method: Balb/C mice were transplanted with the 66cl-4-GFP cell line and in vivo antitumor activity was assessed for CB 1954 (141 mg/kg), TQ (10 mg/kg), and a combination of CB 1954 and TQ. Changes in tumor size and body weight were measured for each treatment. Histological examination of tumors and liver tissue samples was performed using the standard hematoxylin/eosin staining protocol, and serum levels of the liver enzymes AST and ALT were used as biomarkers of hepatotoxicity. Results: Severe liver damage and elevated plasma levels of AST and ALT were observed in the group treated with CB 1954. Treatment of tumor-bearing mice with a combination of CB 1954 and TQ caused a significant regression in tumor size and induced extensive necrosis in these tumors. The combination also protected the liver from drug-induced damage and reduced the plasma levels of AST and ALT to their normal ranges. Conclusion: These results suggest that the use of TQ with CB 1954 can reduce CB 1954-induced hepatotoxicity and enhance its anticancer activity, indicating the potential use of this combination in clinical studies.