Clinical Efficacy and Safety of Albendazole and Other Benzimidazole Anthelmintics for Rat Lungworm Disease (Neuroangiostrongyliasis): A Systematic Analysis of Clinical Reports and Animal Studies

The safety and efficacy of benzimidazole anthelmintics for the management of rat lungworm disease (neuroangiostrongyliasis) have been questioned regardless of the numerous global experimental animal studies and clinical reports. In this review, 40 of these experimental animal studies and 104 clinical reports are compiled with a focus on albendazole. Among the 144 articles involving an estimated 1034 patients and 2,561 animals, 4.1% were inconclusive or vague regarding the use of benzimidazoles. Of the remaining 138 articles, 90.5% found benzimidazoles to be safe and effective (885 patients; 2,530 animals), 4.3% as safe but ineffective (73 patients; 3 animals), and 5.0% caused adverse reactions (7 patients; 28 animals). Among the clinical reports with a confirmed diagnosis of neuroangiostrongyliasis in which albendazole monotherapy was used, 100% reported high efficacy (743 patients; 479 animals), and in those where albendazole-corticosteroid co-therapy was used, 97.87% were reported to be effective (323 patients; 130 animals).

Potential Hexokinase II Inhibition by Benzimidazole Anthelmintics: Albendazole, Mebendazole and Fenbendazole

The nitrogen heterocycle benzimidazoles have been known to be anthelmintic drugs. Beyond that role, the benzimidazoles exhibit other pharmacological potential as anti-inflammatory, antiulcer, anti-hypertensive and anticancer agents. A growing body of evidence supports the anticancer efficiency via treatment with benzimidazoles. The target proteins for pharmacological effect appear to be cell microtubules. However, it has been reported that the benzimidazoles could inhibit hexokinase II, which is a critical factor in the glycolysis pathway in humans. Here, we discuss on the most common benzimidazoles such as albendazole, mebendazole and fenbendazole and focus on the potential anticancer activities of the target enzyme hexokinase II. This review would give better insight in development of target-specific benzimidazole derivatives as potential anticancer therapeutics.

Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells

Tumor suppressor p53 is mutated in about 50% of cancers. Most malignant melanomas carry wild-type p53, but p53 activity is often inhibited due to overexpression of its negative regulators Mdm2 or MdmX. We performed high throughput screening of 2448 compounds on A375 cells carrying p53 activity luciferase reporter construct to reveal compounds that promote p53 activity in melanoma. Albendazole and fenbendazole, two approved and commonly used benzimidazole anthelmintics, stimulated p53 activity and were selected for further studies. The protein levels of p53 and p21 increased upon the treatment with albendazole and fenbendazole, indicating activation of the p53–p21 pathway, while the levels of Mdm2 and MdmX decreased in melanoma and breast cancer cells overexpressing these proteins. We also observed a reduction of cell viability and changes of cellular morphology corresponding to mitotic catastrophe, i.e., G2/M cell cycle arrest of large multinucleated cells with disrupted microtubules. In summary, we established a new tool for testing the impact of small molecule compounds on the activity of p53 and used it to identify the action of benzimidazoles in melanoma cells. The drugs promoted the stability and transcriptional activity of wild-type p53 via downregulation of its negative regulators Mdm2 and MdmX in cells overexpressing these proteins. The results indicate the potential for repurposing the benzimidazole anthelmintics for the treatment of cancers overexpressing p53 negative regulators.