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.
Highlights
Pancreatic cancer (PC) is one of the most fatal tumors worldwide, with a very poor overall survival and a 5-year survival rate of less than 6% [1]
Parbendazole showed the lowest IC50 values as compared to other benzimidazoles tested in both cell lines (Figure 1C), suggesting that the specific substituent at the C5 might be relevant for anti-proliferative activities
Considering that DNA damage could relate with apoptosis and that in a previous study parbendazole was shown to induce such damage in osteosarcoma and cervix adenocarcinoma cell lines [30], we explored whether parbendazole treatment could elicit DNA damage response in AsPC-1 and Capan-2 cell lines (Figure 5C and Figure S3)
Summary
Pancreatic cancer (PC) is one of the most fatal tumors worldwide, with a very poor overall survival and a 5-year survival rate of less than 6% [1]. Incidence and mortality rates for PC are rising according to GLOBOCAN 2018 estimates [2]. Its dismal prognosis is due to the small fraction of patients eligible to radical surgery (15–20%) and to the limited response to standard chemotherapy regimens [1]. Chemotherapeutic options include gemcitabine monotherapy, or combination strategies based on gemcitabine plus nab-paclitaxel, or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin). Even combination strategies offer a limited survival advantage for PC patients as compared to single agents and they are often accompanied by serious side effects. More effective and less toxic drugs to be employed in PC treatment are needed
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