Antitumor Effect of Albendazole on Cutaneous Squamous Cell Carcinoma (SCC) Cells

Abstract

Drug repurposing and/or repositioning is an alternative method to develop new treatment for certain diseases. Albendazole was originally developed as an anthelmintic medication, and it has been used to treat a variety of parasitic infestations. In this study, we investigated the antitumor effect of albendazole and putative action mechanism. Results showed that albendazole dramatically decreased the cell viability of SCC cell lines (SCC12 and SCC13 cells). Albendazole increased apoptosis-related signals, including cleaved caspase-3 and PARP-1 in a dose-dependent fashion. The mechanistic study showed that albendazole induced endoplasmic reticulum (ER) stress, evidenced by increase of CHOP, ATF-4, caspase-4, and caspase-12. Pretreatment with ER stress inhibitor 4-PBA attenuated albendazole-induced apoptosis of SCC cells. In addition, albendazole decreased the colony-forming ability of SCC cells, together with inhibition of Wnt/β-catenin signaling. These results indicate that albendazole shows an antitumor effect via regulation of ER stress and cancer stemness, suggesting that albendazole could be repositioned for cutaneous SCC treatment.

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

“…Supplementary Table 1 ( 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 ) summarizes the antitumorigenicity of benzimidazole anthelmintics on cancer cell lines. Benzimidazole anthelmintics inhibit the progression of cancer through a variety of mechanisms.…”

“…The benzimidazole anthelmintics induced cellular stress through the accumulation of ubiquitylated proteins and increased ROS levels, C/EBP homologous protein (CHOP), activating transcription factor (ATF) 4, and caspase-4/12 as endoplasmic reticulum (ER) stress markers ( 72 ).…”

Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer

“…Finally, fenbendazole and albendazole are used commonly in veterinary and human medicine as anti-parasitic and anti-fungal agents (46), mainly by inhibiting tubulin polymerization (47,48). Matched with our drug screen data, recent studies have also shown their anti-tumor activity in different human cancer cells (28,37,38,(49)(50)(51). Further studies will be required to elucidate the common mechanism(s) of action shared by these drugs (if any) in exhibiting preferential cytotoxicity towards highly metastatic prostate cancer cells when compared to the poorly metastatic cells.…”

Repositioning of Antiparasitic Drugs for Tumor Treatment

“…In fact, ABZs can induce apoptosis in other ways. According to a study on cutaneous squamous cell carcinoma, ABZs increase apoptosis-related signals by inducing endoplasmic reticulum (ER) stress, and pretreatment with the ER stress inhibitor 4-PBA attenuates ABZ-induced apoptosis ( 56 ). Furthermore, in human leukemia U937 cells, ABZs increase MAPK phosphorylation and upregulate TNF-α expression, thus inducing apoptosis.…”