Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer

Abstract

The five-year survival rate for metastatic pancreatic cancer is currently only 3%, which increases to 13% with local invasion only and to 39% with localized disease at diagnosis. Here we evaluated repurposed mebendazole, an approved anthelminthic drug, to determine how mebendazole might work at the different stages of pancreatic cancer formation and progression. We asked if mebendazole could prevent initiation of pancreatic intraepithelial neoplasia precursor lesions, interfere with stromal desmoplasia, or suppress tumor growth and liver metastasis. In both the Kras LSL.G12D/+ ; Pdx1-Cre (KC) mouse model of caerulein-induced inflammatory pancreatitis and the Kras LSL.G12D/+ ; Tp53 R172H/+ ; Pdx1-Cre (KPC) mouse model of advanced pancreatic cancer, mebendazole significantly reduced pancreas weight, dysplasia and intraepithelial neoplasia formation, compared to controls. Mebendazole significantly reduced trichrome-positive fibrotic connective tissue and α-SMA-positive activated pancreatic stellate cells that heralds fibrogenesis. In the aggressive KPC model, mebendazole significantly suppressed pancreatic tumor growth, both as an early and late intervention. Mebendazole reduced the overall incidence of pancreatic cancer and severity of liver metastasis in KPC mice. Using early models of pancreatic cancer, treatment with mebendazole resulted in less inflammation, decreased dysplasia, with the later stage model additionally showing a decreased tumor burden, less advanced tumors, and a reduction of metastasis. We conclude that mebendazole should be investigated further as a component of adjuvant therapy to slow progression and prevent metastasis, and well as for primary prevention in the highest risk patients.

Mebendazole, an anti-helminth drug, suppresses inflammation, oxidative stress and injury in a mouse model of ulcerative colitis

“…Previous data indicated the potency of mebendazole to reduce fibrotic mediators. In a model of pancreatic cancer, Williamson et al reported that mebendazole could decrease fibrotic content in trichrome-stained tissues accompanied by a reduction in α-SMA 22 . Another study also revealed that MBZ reduced the secretion of ECM proteins such as collagens 23 .…”

“…MBZ elicits anti-inflammatory and anti-fibrotic effects in different cell lines and animal models via down-regulation of the mitogen-activated protein kinase (MAPK) 18 , 19 , nuclear factor- kappa B (NF-κB) 20 , cyclooxygenase 2 (COX2) 21 and TGF-β signaling pathways 19 . It also acts as an anti-fibrotic by reducing alpha-smooth muscle actin (α-SMA) levels 22 and collagen release from cells 23 . We aimed to evaluate the therapeutic efficacy of mebendazole in a murine DSS-induced colitis model either alone or in combination with sulfasalazine, a standard therapy for UC.…”

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications

“…More recent discoveries uncovered the heterogeneity of metabolic reprogramming in cancer cells to also include increases in oxidative phosphorylation and the use of alternative carbon sources (i.e., glutamine, fatty acids, and serine). Various studies have revealed a metabolic regulation system between cancer cells, immune cells, and stroma and have demonstrated the targetability of these metabolic shifts in preventing disease progression (151)(152)(153)(154)(155)(156)(157)(158). Surprisingly, studies have also revealed regulation and correlation between metabolic shifts and cytoskeletal proteins in cancer.…”

Mebendazole Impedes the Proliferation and Migration of Pancreatic Cancer Cells through SK1 Inhibition Dependent Pathway

“…The Food and Drug Administration (FDA) has approved the drug mebendazole (MBZ), which was first developed to manage helminthic parasites. In a recent study, it has reportedly been shown to have an anticancer effect on various cancer types in vitro and in vivo [ 15 , 16 , 17 ]. MBZ’s primary mechanism of action is the depolymerization of tubulin, although other investigations have found that its derivative, Fenbendazole, destabilizes tubulin polymerization by stabilizing P53 and causing apoptosis [ 18 , 19 ].…”

“…The metastasis of PDAC can be decreased by MBZ alone or in combination [ 17 ]. In vivo studies have shown that MBZ has tumor-suppressive effects in early and late pancreatic cancer models and reduces metastasis to other organs [ 15 ]. Based on these studies, MBZ alone or in combination with other anticancer drugs can be applied as a therapeutic agent for PDAC.…”