The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

Abstract

Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents. Repurposing of non-anticancer drugs may expand the repertoire of effective molecules. Studies on repurposing of benzimidazole-based anthelmintics in PC and on their interaction with agents approved for PC therapy are lacking. We analyzed the effects of four Food and Drug Administration (FDA)-approved benzimidazoles on AsPC-1 and Capan-2 pancreatic cancer cell line viability. Notably, parbendazole was the most potent benzimidazole affecting PC cell viability, with half maximal inhibitory concentration (IC50) values in the nanomolar range. The drug markedly inhibited proliferation, clonogenicity and migration of PC cell lines through mechanisms involving alteration of microtubule organization and formation of irregular mitotic spindles. Moreover, parbendazole interfered with cell cycle progression promoting G2/M arrest, followed by the emergence of enlarged, polyploid cells. These abnormalities, suggesting a mitotic catastrophe, culminated in PC cell apoptosis, are also associated with DNA damage in PC cell lines. Remarkably, combinations of parbendazole with gemcitabine, a drug employed as first-line treatment in PC, synergistically decreased PC cell viability. In conclusion, this is the first study providing evidence that parbendazole as a single agent, or in combination with gemcitabine, is a repurposing candidate in the currently dismal PC therapy.

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 arrested G2/M phase specifically in the cell cycle by increasing phospho-Histone H3 (pH3), cyclin B1, and p27Kip1, while decreasing cyclin A, cyclin D1, cyclin E, CDC25c, and protein phosphatase 2A (PP2A) cα. Although parbendazole arrested G2/M phase, it decreased cyclin B1 in pancreatic cancer cells ( 68 ). The benzimidazole anthelmintics reduced angiogenesis-related proteins, such as hypoxia-induced hypoxia-inducible factor (HIF)-1α and VEGF ( 54 ).…”

Synthesis and evaluation of a large library of nitroxoline derivatives as pancreatic cancer antiproliferative agents

“…After cell attachment, PC cell lines were treated for 48 h with compounds 33 , 40 , or with nitroxoline as indicated. Colonies were fixed when cells in the control vehicle formed colonies consisting of at least 30 cells 31 .…”

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

“…This anthelmintic drug that is only approved for veterinary use, was also studied as a drug-repurposing candidate for the treatment of PDAC as a single agent or in combination therapy. Parbendazole decreased the cell viability and impaired the cell proliferation, clonogenicity and migration in different PDAC cell lines [ 74 ]. It also induced apoptosis, DNA damage, promoted G2/M cell cycle arrest and affected the tubulin distribution [ 74 ].…”

“…Parbendazole decreased the cell viability and impaired the cell proliferation, clonogenicity and migration in different PDAC cell lines [ 74 ]. It also induced apoptosis, DNA damage, promoted G2/M cell cycle arrest and affected the tubulin distribution [ 74 ]. Moreover, when combined with gemcitabine, parbendazole decreased the cell viability in a dose-dependent manner, suggesting a chemosensitizing effect for this anthelmintic drug in PDAC cells [ 74 ].…”