Repurposing Albendazole: new potential as a chemotherapeutic agent with preferential activity against HPV-negative head and neck squamous cell cancer

Ghasemi, Farhad; Black, Morgan; Vizeacoumar, Frederick S.; Pinto, Nicole; Ruicci, Kara M.; Le, Carson Cao Son Huu; Lowerison, Matthew R.; Leong, Hon S.; Yoo, John; Fung, Kevin; MacNeil, Danielle; Winquist, Eric; Mymryk, Joe S.; Boutros, Paul C.; Datti, Alessandro; Barrett, John W.; Nichols, Anthony C.

doi:10.18632/oncotarget.17292

Cited by 32 publications

(23 citation statements)

References 27 publications

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“…There has been increasing evidence that benzimidazoles are attractive compounds for cancer therapy. Antiproliferative activity of ABZ and other benzimidazoles was described in a broad spectrum of cancer cell lines such as hepatocellular [18], colorectal [19], human HPV-negative HNSCC [23], as well as in melanoma cell lines. Doudican et al demonstrated that mebendazole selectively induces Bcl2-mediated apoptosis in melanoma cells but not in melanocytes [24].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…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.…”

Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

2020

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The development of refractory tumor cells limits therapeutic efficacy in cancer by activating mechanisms that promote cellular proliferation, migration, invasion, metastasis, and survival. Benzimidazole anthelmintics have broad-spectrum action to remove parasites both in human and veterinary medicine. In addition to being antiparasitic agents, benzimidazole anthelmintics are known to exert anticancer activities, such as the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, anti-angiogenesis, and blockage of glucose transport. These antitumorigenic effects even extend to cancer cells resistant to approved therapies and when in combination with conventional therapeutics, enhance anticancer efficacy and hold promise as adjuvants. Above all, these anthelmintics may offer a broad, safe spectrum to treat cancer, as demonstrated by their long history of use as antiparasitic agents. The present review summarizes central literature regarding the anticancer effects of benzimidazole anthelmintics, including albendazole, parbendazole, fenbendazole, mebendazole, oxibendazole, oxfendazole, ricobendazole, and flubendazole in cancer cell lines, animal tumor models, and clinical trials. This review provides valuable information on how to improve the quality of life in patients with cancers by increasing the treatment options and decreasing side effects from conventional therapy.

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“…A recent study demonstrated that albendazole induces leukemia cell apoptosis by increasing ROS production in a non-mitotic manner (20). Albendazole has also been reported to inhibit the development of hepatocellular carcinoma (21), as well as that of colorectal (22), ovarian (23), lung (16), breast (24), gastric (25) and head and neck (26) cancer. Although albendazole inhibits the development of prostate cancer when used in combination with other anticancer agents, the mechanism of these anticancer effects have not been evaluated in detail (27).…”

Section: Introductionmentioning

confidence: 99%

Albendazole exerts antiproliferative effects on prostate cancer cells by inducing reactive oxygen species generation

et al. 2021

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Benzimidazole derivatives are used for their antihelmintic properties, but have also been reported to exert anticancer effects. In the present study, the anticancer effects of albendazole on prostate cancer cells were assessed using proliferation, clonogenic and migration assays. To investigate the anticancer mechanisms of albendazole, reactive oxygen species (ROS) levels were measured, and the expression of genes associated with oxidative stress and Wnt/β-catenin signaling was confirmed by reverse transcription-quantitative PCR and western blotting. Albendazole selectively inhibited the proliferation of the PC3, DU145, LNCaP and AT2 prostate cancer cell lines at concentrations that did not affect the proliferation of a normal prostate cell line (RWPE-1). Albendazole also inhibited the colony formation and migration of PC3 and DU145 cells, as well as inducing ROS production. Diphenyleneiodonium chloride, an inhibitor of NADPH oxidase (NOX), one of the sources of ROS, decreased basal ROS levels in the PC3 and DU145 cells, but did not reduce albendazole-associated ROS production, suggesting that ROS production following albendazole treatment was NOX-independent. The anticancer effect was decreased when albendazole-induced ROS was reduced by treatment with antioxidants (glutathione and N-acetylcysteine). Furthermore, albendazole decreased the mRNA expression of CDGSH iron sulfur domain 2, which regulates antioxidant activity against ROS, as well as the antioxidant enzymes catalase, and glutathione peroxidase 1 and 3. Albendazole also decreased the mRNA expression of catenin β1 and transcription factor 4, which regulate Wnt/β-catenin signaling and its associated targets, Twist family BHLH transcription factor 1 and BCL2. The albendazole-related decrease in the expression levels of oxidative stress-related genes and Wnt/β-catenin signaling proteins was thought to be associated with ROS production. These results suggest that the antihelmintic drug, albendazole, has inhibitory effects against prostate cancer cells in vitro. Therefore, albendazole may potentially be used as a novel anticancer agent for prostate cancer.

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Repurposing Albendazole: new potential as a chemotherapeutic agent with preferential activity against HPV-negative head and neck squamous cell cancer

Cited by 32 publications

References 27 publications

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

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

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

Albendazole exerts antiproliferative effects on prostate cancer cells by inducing reactive oxygen species generation

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