Colorectal cancer (CRC) is one of the most leading causes of cancer-related death in the world because most of cases are diagnosed in advanced stages, when the development of resistance to chemotherapy is more frequent. To face this situation, new therapeutic drugs are desperately needed for patients with advanced cancer, but making safe and efficacious drugs remains expensive and time consuming. Given the high attrition rates, substantial costs and slow pace of new drug discovery and further development, repurposing of 'old' drugs is increasingly becoming an attractive proposition. The objective of this study was to perform a high-throughput screen (HTS) of an FDA-approved drug library (1622 compounds) to specifically identify candidates that can significantly reduce the cell survival of colon cancer cells. Among all, Albendazole which is an anthelmintic drug demonstrated promising in vitro efficacy against colon cancer cells with relatively low toxicity in normal cells. Albendazole is known to bind to the colchicine-sensitive site of β-tubulin, inhibiting their polymerization into microtubules. The decrease in microtubules in the intestinal cells of the parasites decreases their absorptive function, especially the uptake of glucose by the adult and larval forms of the parasites, and also depletes glycogen storage. Insufficient glucose results in insufficient energy for the production of adenosine triphosphate (ATP) and thus parasite dies eventually during helminthic infection. Here, we determined to molecular mechanism/s by which Albendazole regulates colon cancer cell viability. To explore the global changes in colon cancer cells, we performed mass spectrometry analysis in colon cancer cells treated with Albendazole. One of the major proteins which was downregulated by Albendazole was RNF20. RNF20 is a E3 ubiquitin ligase catalyzing histone H2B monoubiquitination, interacts with the motor protein Eg5 during mitosis and participates in spindle assembly. Inhibition of these proteins induces apoptosis by interfering with antiapoptotic proteins Bcl2 family and arrests cells remarkably at G2/M phase in colon cancer cells. Furthermore, Albendazole inhibits invasion and colony formation in vitro, induced apoptosis in tumoroids derived from APCmin mice (Spontaneous colon cancer model) and xenograft tumor formation in vivo. These results indicate that albendazole may have therapeutic potential in colon cancer and provide the framework for future studies of albendazole in CRC.
Citation Format: Iram Fatima, Rizwan Ahmad, Saiprasad Gowrikumar, Susmita Barman, Rafay Abu, Vikas Kumar, Amar B. Singh, Punita Dhawan. Albendazole enhances apoptosis through targeting RNF20/Eg5 interaction in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 936.