Table 1.

Anti-tumor effects of anthelmintic drugs in malignancies of the digestive apparatus.

Drug	Cancer Type	Observation	Ref.
Mebendazole	Gastric cancer	Inhibition of cell growth and invasion of a human malignant cell line derived from a primary gastric tumor, whether used alone or in combination 5-FU	[23]
Mebendazole	CRC	Cytotoxic activity against CRC cell lines (HCT-116, RKO, HT29, HT-8 and SW626)	[24]
Mebendazole	CRC	Reduction of the number and size of intestinal microadenomas in Apcmin/+ 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. Such effect was associated with cyclin B1 and cyclin D1 down-regulation	[29,32]
Flubendazole	CRC	Impairment of phosphorylation/activity of NF-kB in SW480 and SW620 cell lines, suppression of the expression of metastatic markers as well as cell migration	[33]
Niclosamide	CRC	Inhibition of the Wnt/β-catenin signaling pathway in the human CRC cell lines HCT-116, HT-29 and Caco2 by down-regulation of Dishevelled-2. Anti-cancer effects in CRC cells isolated by surgical resection of metastatic disease as well as in NOD/SCID mice implanted with human CRC cell-derived xenografts	[34]
Niclosamide	CRC	Anti-cancer effects on CRC mediated by the induction of autophagy	[35]
Niclosamide	CRC	Anti-proliferative and pro-apoptotic effects on SW480, SW620 and CC531 cells by affecting the formation of β-catenin-Bcl9-LEF/TCF triple-complex and inducing c-jun expression	[36]
Niclosamide	HCC	Cell growth inhibition and induction of apoptotic cell death in HepG2 and QGY7701 cell lines by eliciting ER stress	[37]
Niclosamide	HCC	Impairment of proliferation and induction of apoptosis in HepG2, QGY-7703 and SMMC-7721 cell lines by negatively affecting the phosphorylation/activity of the oncogenic transcription factor STAT3	[38]
Niclosamide	Esophageal cancer	Suppression of STAT3 signaling pathway resulting in the arrest of esophageal adenocarcinoma cells (BE3) and esophageal squamous cell carcinoma cells (CE48T and CE81T) in the G0/G1 phase of the cell cycle	[39]
NiclosamideEthanolamine	HCC	Cytostatic effect on HCC cells and impairment of cell migration, whether used alone or in combination with oxyclozanide	[40]
Niclosamide Ethanolamine	CRC	Reduction of intestinal polyp formation in Apcmin/+ mice. Decrease of hepatic metastasis in a mouse model of CRC metastasis	[40]
Rafoxanide	CRC	Selective induction of ER stress in HCT-116 and DLD1 cells associated with cyclin D1 protein down-regulation, accumulation of cells in the G0/G1 phase and subsequent caspase-dependent apoptosis. Ani-mitogenic effect in human CRC explants. Reduction of both number and size of neoplastic lesions in Apcmin/+ mice	[41]
Rafoxanide	CRC	Induction of autophagy and DAMPs (i.e., ecto-calreticulin exposure, ATP/HMGB1 release) in HCT-116 and DLD1 cells, resulting in immunogenic cell death. Reduction of tumor growth in vaccination experiments in vivo using immunocompetent mice and syngeneic cancer cells	[42]
Rafoxanide	Gastric cancer	Arrest of gastric cancer cells in the G0/G1 phase of the cell cycle, induction of autophagy and apoptosis through the inhibition of the PI3K/Akt pathway both in vitro and in vivo	[43]
Closantel	Liver cancer, pancreatic cancer	Cytostatic effect in zebrafishes xenotransplanted with human liver and pancreatic cancer cells	[44]
Nitazoxanide	CRC	Induction of apoptosis in CRC cell lines in a GSTP1-dependent manner	[45]
Nitazoxanide	CRC	Inhibition of mitochondrial respiration and mTOR pathway in HCT-116- and HT-29-derived spheroids. Suppression of tumor growth in combination with Irinotecan in a mouse xenograft model	[46]
Nitazoxanide	CRC	Anti-cancer activity on CRC cells via the impairment of Wnt/β-catenin signaling pathway	[47]
Nitazoxanide derivative(RM4819)	CRC	Cell cycle arrest and suppression of mitochondrial complex III activity. Inhibition of the proliferation of intestinal tumoroids	[48]
Ivermectin	CRC	Inhibition of Wnt-TCF pathway in DLD1 and Ls174T cells. Blockade of colon cancer stem cell self-renewal. Impairment of the growth of DLD1- and HT-29-derived xenografts in nude mice in a TCF-dependent fashion	[49]
Ivermectin	Gastric cancer	Suppression of MKN1 cell growth in vitro and in vivo through the inhibition of the nuclear expression of YAP1	[50]
Ivermectin	CCA	Induction of S-phase cell cycle arrest and apoptotic cell death in both gemcitabine-sensitive (KKU214) and gemcitabine-resistant (KKU214GemR) CCA cell lines	[51]
Praziquantel	CRC	Synergistic negative effect on DLD1 cell growth and viability, associated with XIAP down-regulation, in combination with paclitaxel	[52]
Pyrvinium pamoate	Pancreatic cancer	Cytotoxic effect on PANC-1 cells cultured under glucose starvation associated with the inhibition of Akt phosphorylation. Anti-tumor activity in vivo in a hypovascular pancreatic cancer model where immunocompromised mice were xenografted with PANC-1 cells	[53]
Pyrvinium pamoate	Pancreatic cancer, CRC	Impairment of glucose starvation-driven transcriptional activation of UPR-related genes (e.g., GRP78, GRP94, XBP-1, ATF4). Anti-tumor activity in nude mice transplanted with either HCT-116 or the pancreatic cancer cell line AsPC-1 in combination with doxorubicin	[54]
Pyrvinium pamoate	CRC	Inhibition of Wnt/β-catenin signaling in HCT-116 and SW480 cells via interaction with CK1α and pygopus down-regulation	[55]
Pyrvinium pamoate	CRC	Reduction of intestinal adenoma formation in Apcmin/+ mice through the inhibition of the Wnt signaling	[56]
Pyrvinium pamoate	CRC	Synergistic anti-cancer effect on HCT-116 and SW620 cell lines in combination with 5-FU. Inhibition of the Wnt signaling in HCT-116 and SW620 cells as well as in human CRC explants. Impairment of liver metastases formation in nude mice injected with HCT-116 in the portal vein	[57]
Piperazine derivative(AK301)	CRC	Impairment of tubulin polymerization and induction of mitotic arrest in HT-29 and HCT116 cells. Increase of the susceptibility to TNF-α-mediated apoptosis	[58]
Piperazine derivative(BK1000S7)	HCC	Blockade of HepG2 and SK-Hep1 cell growth upon cyclin D1 down-regulation. Induction of apoptosis via caspase-3 and PARP-1 protein cleavage, impairment of AKT/ERK kinase phosphorylation and survivin expression	[59]

Abbreviations: CRC: colorectal cancer; 5-FU: 5-fluorouracil; APC: adenomatous polyposis coli; COX: cyclooxygenase; HCC: hepatocellular carcinoma; MAPK: mitogen-activated protein kinase; NF-kB: nuclear factor kB; NOD: non-obese diabetic; SCID: severe combined immunodeficient; LEF: lymphoid enhancer factor; TCF: transcription factor T-cell factor; ER: endoplasmic reticulum; STAT3: signal transducer and activator of transcription 3; DAMP: damage-associated molecular pattern; ATP: adenosine triphosphate; HMGB1: high mobility group box 1; PI3K: phosphatidylinositol 3-kinase; GSTP1: glutathione-S-transferase P1; mTOR: mammalian target of rapamycin; YAP1: yes-associated protein 1; CCA: cholangiocarcinoma; CK1: casein kinase 1; TNF: transforming necrosis factor; PARP: poly(ADP-ribose) polymerase; ERK: extracellular signal-regulated kinase.