Mebendazole augments sensitivity to sorafenib by targeting MAPK and BCL-2 signalling in n-nitrosodiethylamine-induced murine hepatocellular carcinoma

Abstract

Sorafenib (SO) is a multi-kinase inhibitor that targets upstream signals in the MAPK pathway. Drug resistance and transient survival benefits are the main obstacles associated with SO treatment in Hepatocellular carcinoma (HCC) patients. Mebendazole (MBZ), an anthelmintic agent, has demonstrated activity against various cancer types. Therefore, we aimed to investigate the possible mechanisms of MBZ other than its anti-tubulin activity. MBZ (100 mg/kg/day, P.O.) was administered to N-nitrosodiethylamine-induced HCC mice as a monotherapeutic agent or in combination with SO. Our results revealed that MBZ decreased AFP levels, improved liver function and histology and increased survival in HCC mice, particularly when administered in combination with SO. MBZ also reduced hepatic inflammation and fibrogenesis as evidenced by reductions in TNF-α and TGF-β1 levels, respectively. Increased hepatic caspases-3 and -9 and decreased BCL-2 levels suggest induced-cell death. In addition, MBZ demonstrated anti-angiogenic, anti-metastatic, and anti-proliferative effects, as indicated by reduced VEGF levels, MMP-2:TIMP-1 ratios, and reduced cyclin D1 levels and Ki67 immunostaining, respectively. Our main finding was that MBZ targeted downstream signal of the MAPK pathway by inhibiting ERK1/2 phosphorylation. Targeting downstream MAPK signalling by MBZ and upstream signalling by SO is a novel approach to minimizing resistance and prolonging survival.

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.…”

“…Among MAPK signaling, benzimidazole anthelmintics inhibited ERK activation ( 14 51 ) but increased p38 and c-Jun N-terminal kinases (JNK) activations ( 38 55 ). As benzimidazole anthelmintics increased ELK1/serum response factor (SRF) to activate the Fos family, AP-1 also was activated, likely due to the activation of the Jun family from increased pJNK with the activated Fos family ( 45 ).…”

“…We summarized the antitumorigenicity of benzimidazole anthelmintics in animal tumor models ( Supplementary Table 2 ) ( 4 8 11 12 13 14 15 16 17 20 27 28 29 30 34 35 36 37 39 45 47 51 52 54 55 56 57 61 63 64 65 66 69 70 71 74 75 76 78 79 80 92 93 94 ). Benzimidazole anthelmintics have been shown to inhibit the tumor growth in animals, which have been well-tolerated without significant side effects during the experimental period.…”

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

“…Reduction of the number and size of intestinal microadenomas in Apc min/+ mice, once used in combination with sulindac, through the inhibition of MYC and COX2 pathways, cytokine release and angiogenesis [25] Mebendazole CRC Induction of lung and lymph node metastases remission as well as partial liver metastases remission in a patient with refractory metastatic colon cancer [26] Mebendazole HCC Inhibition of the MAPK pathway in vitro and in vivo, whether used alone or in combination with Sorafenib, and improvement of liver function in an animal model of HCC [27] Albendazole CRC Cytostatic effect on HT29 cells in vitro and reduction of cancer growth in nude mice bearing intraperitoneal HT29-derived tumors [28] Albendazole CRC Anti-proliferative effects on SW480, SW620, HCT8 and Caco2 cells, especially when used in combination with paclitaxel [29] Albendazole HCC Cytostatic effects on rat, mice and human HCC cells. Reduction of tumor growth in nude mice inoculated with SK-HEP1 cells [30] Albendazole Pancreatic cancer Cytostatic and pro-apoptotic effects on PANC-1 and SW1990 cells in vitro and in a mouse xenograft model [31] Flubendazole CRC Anti-proliferative effect on SW480, SW620, HCT8, and Caco2 cell lines, also in combination with paclitaxel.…”

“…MBZ showed anti-cancer properties in the treatment of hepatocellular carcinoma (HCC) as well. In particular, MBZ (0.5–5 μmol/L) negatively targeted the MAPK pathway—by reducing the expression of p-MEK1/2 and p-ERK1/2—whether used alone or in combination with the chemotherapeutic drug sorafenib, and improved liver function (when administered at 100 mg/kg/day) in an animal model of HCC [ 27 ]. MBZ is currently being employed in clinical trials for the treatment of gastrointestinal cancers.…”