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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates and requires the development of highly efficacious medications that can improve the efficiency of existing treatment methods. In particular, in PDAC, resistance to conventional chemotherapy reduces the effectiveness of anticancer drugs, decreasing the therapeutic efficiency. Sphingosine 1-phosphate (S1P), produced by sphingosine kinase (SK), plays a vital role in cancer growth, metastasis, chemotherapy, and drug resistance. Focusing on the structural characteristics of mebendazole (MBZ), we studied whether MBZ would affect metastasis, invasion, and drug resistance in cancer by lowering S1P production through inhibition of SK activity. MBZ selectively inhibited SK1 more than SK2 and regulated the levels of sphingolipids. MBZ inhibited the proliferation and migration of cancer cells in other PDAC cell lines. To determine whether the effect of MBZ on cancer cell growth and migration is S1P-mediated, S1P was treated, and the growth and migration of cancer cells were observed. It was found that MBZ inhibited S1P-induced cancer cell growth, and MBZ showed a growth inhibitory effect by regulating the JAK2/STAT3/Bcl-2 pathway. The phosphorylation of focal adhesion kinase (FAK), a transcription factor that regulates migration, was inhibited by MBZ, so it was found that the effect of MBZ regulates the migration of cancer cells through the S1P/FAK/vimentin pathway. In conclusion, our study suggests that the anthelmintic MBZ can be used as a potential therapeutic agent for treating PDAC and for structural synthesis studies of its analogs.

Transcriptome and Lipidomic Analysis Suggests Lipid Metabolism Reprogramming and Upregulating SPHK1 Promotes Stemness in Pancreatic Ductal Adenocarcinoma Stem-like Cells

“…Another study also demonstrated that SPHK1 upregulation may play a potential role in early neoplastic transformation of inflammatory lesions in long-standing chronic pancreatitis patients [71]. Mebendazolee was proved to be used as a potential therapeutic agent for treating PDAC, because it selectively inhibited SPHK1 more than SPHK2 and regulated the levels of sphingolipids [62]. In addition, the inhibitor of SPHK1 was reported to be effective in the combination treatment of PDAC [72], and can enhance the therapeutic effect of gemcitabine [73].…”

“…Ceramide can be converted to ceride-1-phosphate (C1P) [60] and SM [58], respectively, and is also utilized as a precursor for the generation of glycosphingolipids (GSL) including glucosylceramide and lactosylceramide [61]. Ceramide is hydroxylated by ceramidases (CDases) to yield sphingosine, which is phonologically late, by SPHK1 (also known as SK1) or SPHK2 (also known as SK2) to generate S1P [62]. In our study, we observed a slight increase in ceramide levels in TRCs, which may be related to the active metabolism of ceramide due to its role as a substrate for generation of sphingolipids with pro-survival functions.…”

Drug repurposing for cancer therapy

“…160 MBZ has also been shown to inhibit tumor growth via the JAK2/STAT3/ Bcl-2 signaling pathway, while other studies have indicated that MBZ might modulate cancer cell migration through the S1P/FAK/ vimentin pathway. 161 MBZ has also been found to restrict the migratory and invasive tendencies of glioblastoma cells, and concurrently modulate pivotal markers in the EMT, suggesting a potential role for MBZ in mitigating glioblastoma metastasis. In oral squamous cell carcinoma, MBZ was found to downregulate specific proteins and enzymes, including FAK, Rho-A, and Rac1…”