Veterinary Antiparasitic to Human Anticancer

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1		Jeongik Lee	--	3584	2022-04-29 05:21:52	\|
2	format change	Peter Tang	Meta information modification	3584	2022-04-29 09:36:12	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms23084315

Cancer is an extensive disease and the most common cause of morbidity and mortality worldwide. It is characterized by a deregulation of the cell cycle, which primarily results in a progressive loss of control of cellular growth and differentiation. The repurposing of veterinary antiparasitic drugs for the treatment of cancer is gaining traction, as supported by existing literature. A prominent example is the proposal to implement the use of veterinary antiparasitics such as benzimidazole carbamates and halogenated salicylanilides as novel anticancer drugs. These agents have revealed pronounced anti-tumor activities and gained special attention for “double repositioning”, as they are repurposed for different species and diseases simultaneously, acting via different mechanisms depending on their target. As anticancer agents, these compounds employ several mechanisms, including the inhibition of oncogenic signal transduction pathways of mitochondrial respiration and the inhibition of cellular stress responses.

drug repurposing antiparasitic benzimidazole carbamates halogenated salicylanilides cancer therapy

1. Introduction

Cancer is an extensive disease and the most common cause of morbidity and mortality worldwide. It is characterized by a deregulation of the cell cycle, which primarily results in a progressive loss of control of cellular growth and differentiation ^[1]. Although there are numerous ongoing studies on anticancer therapy, with many lead candidates at various phases of preclinical or clinical research, only 5% of potential anticancer therapies entering phase I clinical trials have been approved and have entered the market ^[2]. The standard cancer treatments include surgery, immunotherapy, radiation, and chemotherapy. Currently, chemotherapy is one of the most efficient and potent strategies used to treat malignant tumors. However, the development of multidrug resistance to chemotherapeutics has become a huge impediment to successful cancer treatment. Clearly, new therapeutic alternatives are required to improve cancer diagnosis and treatment. Prior to being marketed as a new drug, the lead compounds face many hurdles during preclinical and clinical studies to ensure their quality, safety, dosage, and efficacy. Clinical trials are costly and time-consuming, requiring ten to fifteen years of dedicated research. The entire development process of getting a single candidate compound onto the market is hindered by the exorbitant costs (approximately $1–$2.5 billion) associated with the necessary trials required for U.S. Food and Drug Administration (FDA) approval ^[3].

Drug repurposing has gained recognition in the last decade, enabling existing pharmaceutical products to be reconsidered for alternative applications. It has reduced the risk of a drug failing to reach the market, owing to the low burden of adverse effects, the attenuation of the economic load, and the expedition of the approval process ^[4]. It can also offer an improved risk versus reward trade-off as it shortens the timeline of the drug development process and is also economically feasible when compared to other drug development strategies ^[5]. Additionally, the preclinical results obtained from the use of repurposed drugs may expedite the process of the preclinical to clinical translation of cancer treatment ^[6].

2. BZ Carbamates

BZ antiparasitics are a group of heterocyclic aromatic organic compounds that are extensively used in both human and veterinary medicines to inhibit internal parasites. Some important BZ drugs include MZ, albendazole (ABZ), fenbendazole (FZ), flubendazole (FLU), triclabendazole, parbendazole, oxibendazole, and ricobendazole. In the last few years, some of these have been successfully investigated for various types of cancers worldwide.

2.1. Mechanism of Action of BZ Carbamates

The molecular mode of action of BZ carbamates involves inhibiting the polymerization of tubulin and facilitating the disruption of microtubules in parasite cells (Figure 1) ^[7]. An in vitro study using the extracts of helminthic and mammalian tubulin has implicated tubulin as the leading molecular target of BZ carbamates ^[8]. Tubulin is pivotal to cell motility, proliferation, and division; the intercellular transport of organelles; the maintenance of cell shape; and the secretion process of cells in all living organisms ^[9]. By blocking microtubule elongation in worms, BZ carbamates perturb glucose uptake in cells. Eventually, the glycogen reserves are exhausted, and their energy management mechanisms are depleted, culminating in the death of the parasites ^[10].

Figure 1. Mechanism of action of benzimidazole (BZ) carbamates targeting tubulin. Tubulin is the leading molecular target of BZ carbamates. They selectively bind to parasitic β-tubulin, promoting their immobilization and death. dapted from “Antibody-Drug Conjugate Drug Release”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates, accessed on 10 March 2022.

2.2. Anticancer Activity of BZ Carbamates

BZ carbamates are cancer cell-selective, causing minimal cytotoxicity in normal cells but increased cytotoxicity in different tumor cells. Several studies have reported that BZ carbamates inhibit the polymerization of mammalian tubulin in vitro. Whether the same effect would be observed in human cells, and if so, whether such targeted efforts could be effective against tumors, are some questions raised by these reports. Lacey et al. first addressed the activity of BZ carbamates against mouse leukemia cells L1210 in 1985 ^[11]. A more thorough inquiry into the antitumor effects of BZ carbamates was carried out; the most promising outcomes of this inquiry are summarized in Table 1. The general pharmacokinetic properties of BZ carbamates are as follows: slow absorption; wide distribution throughout the body; extensive hepatic metabolism; and excretion via urine and feces (Figure 2a). Their common side effects are fever, nausea, vomiting, abdominal discomfort, and hepatotoxicity. The low intestinal absorption rate of BZ carbamates may make it difficult for them to reach concentrations in the systemic circulation effective in treating cancers in humans. Increased bioavailability is necessary to enhance their antitumor effect, making them safe and well tolerable in human and veterinary use.

Figure 2. Pharmacokinetic properties and side effects of veterinary antiparasitic drugs. (a) The BZ carbamate drugs are poorly absorbed; have a wide distribution in the body; show extensive hepatic metabolism; and are excreted via feces and urine. (b) The halogenated salicylanilides (HS) antiparasitic drugs show poor absorption, distribution throughout the body, are poorly metabolized and are excreted in bile, feces, or urine.

Table 1. Anticancer activity of BZ carbamates.

Cell Source	Cell Lines	Procedure of Study	Species	Antiparasitics	Cancer Type	Target Pathway	Reference
Human	Hep G2 and Hep3B	in vitro	Mice	ABZ	HCC	Cytotoxicity	^[12]
Human	Hep G2 and Hep3B, PLC/PRF/5 and SKHEP-1	in vitro	Mice	ABZ	HCC	Tubulin disruption	^[13]
Human	SKHEP-1	in vivo
Rat	HTC, Novikoff	in vitro
Mice	Hep1-6	in vitro
Human	SW480, SW620, HCT8 and Caco2	in vitro	Mice	ABZ, RBZ, FLU	Intestinal cancer	Tubulin disruption	^[14]
Human	HT-29	in vitro	Mice	ABZ	CRC	Apoptosis	^[15]
Human	CEM/dEpoB300	in vitro	Mice	ABZ	Leukemia	Apoptosis	^[16]
Human	1A9Pc TX22	in vitro	Mice	ABZ	OC	Apoptosis	^[17]
Mouse	EMT6	in vitro	Mice	FZ	Mammary carcinoma	Cytotoxicity	^[18]
Mouse	EMT6	in vivo	Mice	FZ	Mammary carcinoma	Cytotoxicity	^[18]
Human	H460 and A549	in vitro	nu/nu mice	FZ	LC	microtubule disruption, p53 activation and down regulation of pivotal glycolytic enzymes	^[19]
Human	H460 and A549	in vivo	nu/nu mice	FZ	LC		^[19]
Human	P493-6	in vitro	SCID mice	FZ	Lymphoma	Tubulin disruption	^[20]
Human	P493-6	in vivo	SCID mice	FZ	Lymphoma	Tubulin disruption	^[20]
Mice	EMT6	in vitro	BALB/c Rw mice	FZ	Mammary carcinoma	Tubulin disruption	^[21]
Mice	EMT6	in vivo	BALB/c Rw mice	FZ	Mammary carcinoma	Tubulin disruption	^[21]
Human	OCI-AML-2	in vitro	SCID mice	FLU	Leukaemia and Myeloma	Tubulin disruption	^[22]
Human	OCI-AML-2	in vivo	SCID mice	FLU	Leukaemia and Myeloma	Tubulin disruption	^[22]
Human	MDA-MB-231, BT-549, SK-BR-3 and MCF-7	in vitro	Mice	FLU	BC	Tubulin disruption	^[23]
Human	MDA-MB-231, BT-549, SK-BR-3 and MCF-7	in vivo	Mice	FLU	BC	Tubulin disruption	^[23]
Human	TNBC cell lines MDA-MB-231 and MDA-MB-468	in vitro	Mice	FLU	BC	Apoptosis	^[24]
Human	TNBC cell lines MDA-MB-231 and MDA-MB-468	in vivo	Mice	FLU	BC	Apoptosis	^[24]
Human	BT474, SK-BR-3, MDA-MB-453, JIMT-1	in vitro	BALB/c mice	FLU	BC	Tubulin disruption	^[25]
Human	BT474, SK-BR-3, MDA-MB-453, JIMT-1	in vivo	BALB/c mice	FLU	BC	Apoptosis	^[25]
Human	HCT116, RKO and SW480	in vitro	BALB/c mice	FLU	CRC	Apoptosis	^[26]
Human	HCT116, RKO and SW480	in vivo	BALB/c mice	FLU	CRC	Apoptosis	^[26]
Human	H295R and SW-13	in vitro	Mice	MZ	Adrenocortical carcinoma	Apoptosis	^[27]
Human	H460, A549, H1299 and WI-38	in vitro	Mice	MZ	LC	Tubulin disruption, Apoptosis	^[28]
Human	H460, A549, H1299 and WI-38	in vivo	Mice	MZ	LC	Tubulin disruption, Apoptosis	^[28]
Human	HCT 116 and RKO	in silico	-	MZ	CC	Tubulin disruption	^[29]
Human	DLD-1, HCT-116, HT-29 and SW480	in vitro	Mice	MZ	CC	Tubulin disruption	^[30]
Human	ACP-02, ACP-03 and AGP-01	in vitro	Mice	MZ	GC	Tubulin disruption	^[31]
Human	ACP-02, ACP-03 and AGP-01	in vivo	Mice	MZ	GC	Tubulin disruption	^[31]
Mouse	GL261	in vitro	C57BL6 Mice	MZ	Brain tumour	Tubulin disruption	^[32]
Mouse	GL261	in vivo	C57BL6 Mice	MZ	Brain tumour	Apoptosis	^[32]
Human	GBM U87-MG, D54, H80, H247, H392, H397, H502 and H566	in vitro	C57BL/6 mice	MZ	Brain cancer	Apoptosis	^[33]
Human	GBM U87-MG, D54, H80, H247, H392, H397, H502 and H566	in vivo
Mouse	GL261	in vivo
Human	D425 MB	in vivo	p53 mice	MZ	Medullo-blastoma	Tubulin disruption	^[34]
Human	293T and hTERT-RPE1	in vitro	nu/nu athymic mice	MZ	Medullo-blastoma	Hedgehog inhibitor	^[35]
Human	293T and hTERT-RPE1	in vivo	nu/nu athymic mice	MZ	Medullo-blastoma	Hedgehog inhibitor	^[35]
Murine	CP2 and SP1	in vitro	BALB/c mice	MZ	PC	Tubulin disruption	^[36]
Murine	CP2 and SP1	in vivo	BALB/c mice	MZ	PC	Tubulin disruption	^[36]
Human	KKU-M213	in vitro	Nude mice	MZ	Bile duct Cancer	Apoptosis	^[37]
Human	KKU-M213	in vivo	Nude mice	MZ	Bile duct Cancer	Apoptosis	^[37]
Human	PANC-1	in vitro	Mice	MZ	Pancreatic cancer	-	^[38]
Human	CAL27 and HCC15	in vitro	Nude mice	MZ	Head and neck cancer	Apoptosis	^[39]
Human	CAL27 and HCC15	in vivo	Nude mice	MZ	Head and neck cancer	Apoptosis	^[39]
Human	SK-Br-3	in vivo	Mice	MZ	BC	Tubulin disruption	^[40]
Human	M-14 and SK-Mel-19	in vitro	Mice	MZ	Melanoma	Tubulin disruption	^[41]
Human	MM622, MM540, D08, MM329, D17, and UACC1097	in vitro	Mice	MZ	Melanoma	Tubulin disruption	^[42]
Human	MM622, MM540, D08, MM329, D17, and UACC1097	in vivo	Mice	MZ	Melanoma	Tubulin disruption	^[42]
Human	NRAS^Q61K	in vitro	Athymic mice	MZ	Melanoma	Apoptosis	^[43]
		in vivo
		in silico
Human	GL261	in vitro	C57BL/6 mice	MZ	Brain cancer	Tubulin disruption	^[44]
Human	GL261	in vivo	C57BL/6 mice	MZ	Brain cancer	Tubulin disruption	^[44]
Human	Burkitt’s lymphoma Ramos cells, Hela cells, PANC-1 cells, and HepG2 cells	in vivo	Zebra-fish	Closantel	Lymphoma, cervical cancer, PC, and LC	Suppression of antiangiogenesis and Closantel	^[45]
Human	Du146	in vitro	Mice	Nic	PC	Inhibition of STAT3 Pathway	^[46]
Human	HEK293 cells	in vitro	Mice	Nic	PC and BC	Inhibition of Wnt/β-catenin Pathway	^[47]
Human	MCF7 and MDA-MB-231	in vitro	NOD/SCID mice	Nic	BC	Apoptosis and downregulation stem pathways	^[48]
Human	MCF7 and MDA-MB-231	in vivo	NOD/SCID mice	Nic	BC	Apoptosis and downregulation stem pathways	^[48]
Human	MDA-MB-231	in vitro	BALB/c nude mice	Nic and cisplatin	BC	Apoptosis and inhibition of Akt, ERK, and Src pathways	^[49]
Human	MDA-MB-231	in vivo	BALB/c nude mice	Nic and cisplatin	BC	Apoptosis and inhibition of Akt, ERK, and Src pathways	^[49]
Human	MDA-MB-468 and MCF-7	in vitro	Mice	Nic	BC	Inhibition of cell motility and STAT3 activity	^[50]
Human	TNBC MDA-MB-231, MDA-MB-468 and Hs578T	in vitro	Athymic nude mice	Nic	BC	Inhibition of Wnt/β-catenin Pathway	^[51]
Human	TNBC MDA-MB-231, MDA-MB-468 and Hs578T	in vivo	Athymic nude mice	Nic	BC	Inhibition of Wnt/β-catenin Pathway	^[51]
Mouse	4T1	in vitro	BALB/c mice	Nic	BC	Apoptosis and suppression of cell migration and invasion	^[52]
Mouse	4T1	in vivo
Human	MDA-MB-231, MDA-MB-468 and MCF-7	in vitro
Human	2LMP, SUM159, HCC1187, and HCC1143	in vitro	NOD/ SCID mice	Nic	BC	Cytotoxicity	^[53]
Human	2LMP, SUM159, HCC1187, and HCC1143	in vivo	NOD/ SCID mice	Nic	BC	Cytotoxicity	^[53]
Human	K562 and KBM5-T315I cells	in vitro	NOD mice	Nic	Chronic myelogenous leukemia	Inhibition of FOXM1/β-catenin Pathway	^[54]
Human	K562 and KBM5-T315I cells	in vivo	NOD mice	Nic	Chronic myelogenous leukemia	Inhibition of FOXM1/β-catenin Pathway	^[54]
Human	HL-60, U937, OCI-AML3, Molm13, MV4-11, and U266 cells	in vitro	BALB/c mice	Nic	Acute myelogenous leukemia	Apoptosis and Inhibition of NF-κB pathway	^[55]
Human	HL-60, U937, OCI-AML3, Molm13, MV4-11, and U266 cells	in vivo	BALB/c mice	Nic	Acute myelogenous leukemia	Apoptosis and Inhibition of NF-κB pathway	^[55]
Human	MCF7	in vitro	Mice	Nic	Adeno-carcinoma	Inhibition of PI3K-dependent signalling	^[56]
	HCC1954	in vitro			Carcinoma
	BT-474	in vivo			Ductal Carcinoma
	MDA-MB-361 and	in vivo			Adeno-carcinoma
	SKBR3 cell	in silico			Adeno-carcinoma
Human	HCT116, SW620, and HT29	in vivo	Mice	Nic	CC	Inhibition of STAT3 phosphorylation	^[57]
Human	HCT116, SW480, DLD1 and 293 cells	in vitro	APC-MIN mice	Nic	CC	Inhibition of Wnt/Snail-mediated EMT	^[58]
Human	HCT116, SW480, DLD1 and 293 cells	in vivo	APC-MIN mice	Nic	CC	Inhibition of Wnt/Snail-mediated EMT	^[58]
Human	HCT116, SW620, LS174T, SW480, and DLD-1	in vitro	NOD/SCID mice	Nic	CC	Inhibition of S100A4-induced metastasis formation	^[59]
		in vivo
		in situ
Human	HT29, HCT116, CaCO2 and MCF-10A	in vitro	NOD/SCID mice	Nic	CC	Inhibition of Wnt/β-catenin Pathway	^[60]
Human	HT29, HCT116, CaCO2 and MCF-10A	in vivo	NOD/SCID mice	Nic	CC	Inhibition of Wnt/β-catenin Pathway	^[60]
Human	HEK293T, U2OS, WIDR, DLD-1, CRC 240, COLO205, CRC57 and HCT116	in vitro	Mice	Nic	CC	Induction of autophagy and inhibition of Wnt/β-catenin Pathway	^[61]
Human	SW480 and SW620	in vitro	Mice	Nic	CC	Reduction of Wnt activity	^[62]
Rodent	CC531	in vivo	Mice	Nic	CC	Reduction of Wnt activity	^[62]
Murine	MC38	in vitro	APC^min/+ mouse	Nic-EN and oxyclozanide	CC	Mitochondrial uncoupling	^[63]
Murine	MC38	in vivo
Human	HCT116	in vitro
Rodent	C2C12	in vitro
Rodent	C2C12	in vivo
Human	SKOV3 and CP70	in vitro	SCID mice	Nic	OC	Induction of metabolic shift to glycolysis	^[64]
Human	SKOV3 and CP70	in vivo	SCID mice	Nic	OC	Induction of metabolic shift to glycolysis	^[64]
Human	OVCAR-3, SKOV-3 and A2780	in vitro	NOD/ SCID mice	Nic	OC	Inhibition of CP70sps and primary OTICs	^[65]
Human	OVCAR-3, SKOV-3 and A2780	in vivo	NOD/ SCID mice	Nic	OC	Inhibition of CP70sps and primary OTICs	^[65]
Human	SKOV3.ip1	in vitro	Mice	Nic	OC	Inhibition of Wnt/β-catenin Pathway	^[66]
Human	SKOV3.ip1	in vivo	Mice	Nic	OC	Inhibition of Wnt/β-catenin Pathway	^[66]
Human	SKOV3 and HO8910	in vitro	Athymic Nude mice	Nic	OC	Mitochondrial Respiration and aerobic glycolysis	^[67]
Human	SKOV3 and HO8910	in vivo	Athymic Nude mice	Nic	OC	Mitochondrial Respiration and aerobic glycolysis	^[67]
Human	A2780ip2, A2780cp20, and SKOV3Trip2	in vitro	SCID mice	Nic	OC	Inhibition of Wnt/β-catenin, mTOR and STAT3 pathways	^[68]
Human	A2780ip2, A2780cp20, and SKOV3Trip2	in vivo	SCID mice	Nic	OC	Inhibition of Wnt/β-catenin, mTOR and STAT3 pathways	^[68]
Human	Tumorspheres	in vitro	Mice	Nic and its analogs in combination with carboplatin	OC	Cytotoxicity	^[69]
Human	Tumorspheres	in vivo	Mice	Nic and its analogs in combination with carboplatin	OC	Cytotoxicity	^[69]
Human	HepG2 and QGY7701	in vitro	Mice	Nic	HCC	Apoptosis and suppression of ATF3 expression	^[70]
Human	NSCLC, NCI-H1299 and HCT116	in vitro	Mice	Nic	LC	Apoptosis through ROS-mediated p38 MAPK-c-Jun activation	^[71]
Human	SK-Hep-1 and Huh7	in vitro	Mice	Nic	HCC	Inhibition of metastasis of HCC, and CD10	^[72]
Human	HCC827, H1650, and H1975	in vitro	Nu/Nu nude mice	Nic	LC	Inhibition of STAT3 phosphorylation	^[73]
Human	HCC827, H1650, and H1975	in vivo	Nu/Nu nude mice	Nic	LC	Inhibition of STAT3 phosphorylation	^[73]
Human	A549/DDP	in vitro	Mice	Nic combined with cisplatin (DDP)	Cisplatin-resistant LC	Apoptosis and reduction of c-myc protein	^[74]
Human	HepG2, QGY-7703 and SMMC-7721	in vitro	Mice	Nic	HCC	Inhibition of cell growth and STAT3 pathway	^[75]
Human	Lung adenocarcinoma (549, EKVX, H358, Hop62, H322M, H522, H838, and H23), large cell lung carcinoma (H460, Hop92), NCSLC (H1299, H810) and small cell LC (H82)	in vitro	Mice	Nic	LC	Reduction in proliferation and inhibition of S100A4 protein	^[76]
Human	U-87 MG	in vitro	Mice	Nic	Glioblastoma	Cell toxicity and inhibition of Wnt/β-catenin, PI3K/AKT, MAPK/ERK, and STAT3	^[77]
Human	TS15-88, GSC11	in vitro	Athymic nude mice	Nic and/or temo-zolomide	Glioblastoma	Inhibition of the expression of epithelial-mesenchymal transition-related markers, Zeb1, N-cadherin, and β-catenin	^[78]
Human	TS15-88, GSC11	in vivo	Athymic nude mice	Nic and/or temo-zolomide	Glioblastoma		^[78]
Human	LN229, T98G, U87(MG), U138, and U373(MG)	in vitro	Rag2^−/−Il2rg^−/− and SCID/ Beige mice	Nic	Glioblastoma	Cytotoxicity and diminished the pGBMs’ malignant potential	^[79]
Human	LN229, T98G, U87(MG), U138, and U373(MG)	in vivo	Rag2^−/−Il2rg^−/− and SCID/ Beige mice	Nic	Glioblastoma	Cytotoxicity and diminished the pGBMs’ malignant potential	^[79]
Human	C4-2B, LNCaP and DU145	in vitro	Mice	Nic with enzalutamide	Enzalutamide resistance PC	Inhibition of migration, invasion and IL6-Stat3-AR pathway	^[80]
Human	LNCaP, VcaP, CWR22Rv1, PC3 and HEK293	in vitro	SCID mice	Nic with enzalutamide	Castration-resistant PC	Inhibition of AR variant and enzalutamide-resistant tumor growth	^[81]
Human	LNCaP, VcaP, CWR22Rv1, PC3 and HEK293	in vivo	SCID mice	Nic with enzalutamide	Castration-resistant PC		^[81]
Human	CaLo, HeLa, SiHa, CasKi, DoTc2, ViBo and C-33A	in vitro	SCID mice	Nic	Cervical cancer	Inhibition of mTOR signaling	^[82]
Human	CaLo, HeLa, SiHa, CasKi, DoTc2, ViBo and C-33A	in vivo	SCID mice	Nic	Cervical cancer	Inhibition of mTOR signaling	^[82]
Human	ESO26, FLO-1, KYAE-1, OE33, SK-GT-4, and OE19	in vitro	SCID mice	Nic	Esophageal cancer	Inhibition of Wnt/β-catenin	^[83]
Human	ESO26, FLO-1, KYAE-1, OE33, SK-GT-4, and OE19	in vivo	SCID mice	Nic	Esophageal cancer	Inhibition of Wnt/β-catenin	^[83]
Human	BE3,CE48T/VGH and CE81T/VGH	in vitro	Mice	Nic	Esophageal cancer	Inhibition of cell proliferation and STAT3 pathway	^[84]
Human	Osteosarcoma cells	in vitro	Mouse	Nic	Osteosarcoma	Apoptosis and target multiple signaling pathways	^[85]
Human	Osteosarcoma cells	in vivo	Mouse	Nic	Osteosarcoma	Apoptosis and target multiple signaling pathways	^[85]
Human	NCI-H295R and SW-13	in vitro	Nu⁺/Nu⁺ mice	Nic	Adrenocortical Carcinoma	Induction of G₁ cell-cycle arrest mitochondrial uncoupling	^[86]
Human	NCI-H295R and SW-13	in vivo	Nu⁺/Nu⁺ mice	Nic	Adrenocortical Carcinoma	Induction of G₁ cell-cycle arrest mitochondrial uncoupling	^[86]
Human	A498 and Caki-1	in vitro	Athymic nude mice	Nic	Renal cell carcinoma	Inhibition of cell proliferation, migration and cell cycle progression	^[87]
Human	A498 and Caki-1	in vivo	Athymic nude mice	Nic	Renal cell carcinoma		^[87]
Human	SCC4 and SCC25	in vitro	Mice	Nic	Oral cancer	Inhibition of cancer stemness, extracellular matrix remodeling, and metastasis through dysregulation Wnt/β-catenin signaling pathway	^[88]
Human	H929, MM1S, U266 and BMSC	in vitro	BALB/c nude mice	RFX	Multiple myeloma	Apoptosis and inhibition of DNA synthesis	^[89]
Human	H929, MM1S, U266 and BMSC	in vivo	BALB/c nude mice	RFX	Multiple myeloma	Apoptosis and inhibition of DNA synthesis	^[89]
Human	A431 and A375	in vitro	BALB/c nude mice	RFX	Skin cancer	Inhibition of CDK4/6	^[90]
Human	A431 and A375	in vivo	BALB/c nude mice	RFX	Skin cancer	Inhibition of CDK4/6	^[90]
Human	HCT-116 and HT-29	in vitro	Apc^min/+ mice	RFX	CRC	Inhibition of cell proliferation	^[91]
Human	HCT-116 and HT-29	in vivo	Apc^min/+ mice	RFX	CRC	Inhibition of cell proliferation	^[91]
Human	HCT-116 and DLD1 cells	in vitro	BALB/c nude mice	RFX	CRC	Induction of ICD of CRC cells	^[92]
Human	HCT-116 and DLD1 cells	in vivo	BALB/c nude mice	RFX	CRC	Induction of ICD of CRC cells	^[92]
Human	SGC-7901 and BGC-823, GES-1	in vitro	BALB/c nude mice	RFX	GC	Apoptosis and inhibition of PI3K/Akt/mTOR signaling pathway	^[93]

PubMed, Google Scholar, and CTD databases were used to summarize the data for the antitumor effects of BZ carbamates. ABZ—albendazole; BC—breast cancer; CC—colon cancer; CRC—colorectal cancer; EMT—epithelial–mesenchymal transition; FZ—fenbendazole; GC—gastric cancer; HCC—hepatocellular carcinoma; ICD—immunogenic cell death; LC—lung cancer; MZ—Mebendazole; Nic—Niclosamide; Nic-EN—Niclosamide ethanolamine; OC—ovarian cancer; PC—prostate cancer; RBZ—Ricobendazole; RFX—Rafoxanide.

2.3. Anticancer Activity of BZ Carbamates in Clinical Models

A pilot study of the effect of ABZ in seven patients with advanced hepatocellular carcinoma and CRC with hepatic metastases refractory to other forms of therapy was performed for 28 days. Patients received ABZ orally (10 mg/kg/day) in two divided doses. The levels of tumor markers, carcinoembryonic antigen, and a-fetoprotein were measured routinely. The parameters of hematological and biochemical indices were also obtained to monitor bone marrow, kidney, and liver toxicities. The results of this research further confirm the tolerance for ABZ in patients, with the only side effect of concern being acute neutropenia in three of the patients. Moreover, ABZ significantly reduced two tumor markers in two patients, while in three other patients the markers were stabilized, demonstrating that ABZ possesses antitumor effects in humans ^[94].

At present, no clinical study on FLU and FZ in human malignancies has been conducted. A more thorough report on clinical trials documenting the antitumor effects of antiparasitic drugs is summarized in Table 2.

Table 2. Application of veterinary antiparasitic drugs in clinical trials used to treat different types of cancers.

Antiparasitics	Cancer Type	Title	Phase	Purpose	Status/Result	Identifier/Ref
ABZ	HCC or CRC	Pilot Study Of Albendazole In Patients With Advanced Malignancy. Effect On Serum Tumor Markers/High Incidence Of Neutropenia	PS	Evaluation of anticancer activity	Stabilization of the disease, but because of neutropenia, treatment was stopped on day 19	^[95]
ABZ	Refractory solid tumors	Phase I Clinical Trial To Determine Maximum Tolerated Dose Of Oral Albendazole In Patients With Advanced Cancer	1	To determine the safety, tolerability, and the maximal tolerated dose. To characterize the pharmacokinetics and preliminary evidence of efficacy.	2400 mg/day from 1200 mg b.d. Decreased plasma VEGF and 16% patients had a tumor marker response with a fall of at least 50%	^[94]
MZ	Adreno-cortical carcinoma	Mebendazole Monotherapy and Long-Term Disease Control in Metastatic Adrenocortical Carcinoma	CS	To describe successful long-term tumor control	Well tolerated, and the associated adverse effects of MZ are minor	^[96]
MZ	CC	Drug Repositioning From Bench To Bedside: Tumour Remission By The Antihelmintic Drug Mebendazole In Refractory Metastatic Colon Cancer	CS	Repositioning drugs for use in advanced CC	No disease-related symptoms were found	^[97]
MZ	Glio- blastoma	Mebendazole In Newly Diagnosed High-Grade Glioma Patients Receiving Temozolomide (Mebendazole)	1	To find the highest dose and the efficiency of MZ to slow the growth of the brain tumor	Active, not recruiting	NCT01729260
MZ	Pediatric Gliomas	A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas	1	To determine the safety and efficacy of MZ	Recruiting	NCT01837862
MZ	GI Cancer	A Clinical Safety and Efficacy Study of Mebendazole on GI Cancer or Cancer of Unknown Origin. (RepoMeb)	1	To determine the safety and efficacy of MZ (ReposMZ)	Terminated (Lack of effect)	NCT03628079
MZ	Cancer of Unknown Origin		2	To determine the safety and efficacy of MZ (ReposMZ)	Terminated (Lack of effect)	NCT03628079
MZ	OC, PC and ovarian epithelial cancer	Study of the Safety, Tolerability and Efficacy of Metabolic Combination Treatments on Cancer (METRICS)	3	To determine the effectiveness of a regimen of selected metabolic treatments for cancer patients and to perform exploratory analysis on the relationship between the degree of response and changes in biochemical markers	Not yet recruiting	NCT02201381
MZ	CC	Mebendazole as Adjuvant Treatment for Colon Cancer	3	MZ as adjuvant treatment for colon cancer	Recruiting	NCT03925662
Nic	CC	A Study of Niclosamide in Patients With Resectable Colon Cancer	1	To determine the maximum tolerated dose (MTD)	Terminated (low accrual)	NCT02687009
Nic	CRC	Drug Trial to Investigate the Safety and Efficacy of Niclosamide Tablets in Patients With Metastases of a Colorectal Cancer Progressing After Therapy (Nikolo)	2	To evaluate the safety and efficacy of oral appliqued Nic	Unknown	NCT02519582
Nic	PC	Niclosamide and Enzalutamide in Treating Patients With Castration-Resistant, Metastatic PC	1	To determine the side effects and best dose of Nic	Completed (No result posted)	NCT02532114
Nic	Metastatic PC	Enzalutamide and Niclosamide in Treating Patients With Recurrent or Metastatic Castration-Resistant PC	1	To determine the best dose and side effects of Nic when given together with enzalutamide	Recruiting	NCT03123978
	Recurrent PC
	Stage IV PC
Nic	Metastatic PC	Abiraterone Acetate, Niclosamide, and Prednisone in Treating Patients With Hormone-Resistant PC	2	To determine the side effects and how well abiraterone acetate, Nic, and prednisone work in treating patients with hormone-resistant PC	Recruiting	NCT02807805
	Recurrent PC
	Stage IV PC

NCBI database was used to inquire about the clinical trials on antitumor effects of antiparasitic drugs. ABZ—albendazole; MZ—mebendazole, Nic—niclosamide, CS—clinical study; CC—colon cancer; CRC—colorectal cancer; HCC—hepatocellular carcinoma; PS—pilot Study.

3. HS

Salicylanilides are a very large group of compounds that show efficient activity against certain types of parasites. Their basic chemical structure consists of a salicylic acid ring and an anilide ring. Examples of HS drugs with potent antihelminthic activity are Nic, rafoxanide (RFX), and closantel.

3.1. Mechanism of Action of HS

The primary mechanism of action of HS was investigated in vitro using houseflies and rat liver mitochondria. The authors found an association with the uncoupling of oxidative phosphorylation that halts the production of ATP. This seems to happen through the suppression of the activity of two enzymes, succinate dehydrogenase and fumarate reductase, and thus impairs the motility of parasites and eventually causes death ^[98]. Several researchers have subsequently confirmed the proposed mechanism in vivo ^[45]^[99].

3.2. Anticancer Activity of HS

Several HS group drugs have been investigated for their effect on cancer in experimental and preclinical models. The pharmacokinetic properties and common side effects of HS drugs are shown in Figure 2b.

3.3. Anticancer Activity of HS in Clinical Models

Nic underwent clinical trials in patients with resectable colon cancer in 2017, but was terminated because of the low enrolment rate (NCT02687009). Two other clinical studies are currently underway to test the anticancer effects of Nic in patients with FAP (NCT04296851) and progression of metastases of colorectal cancer after therapy (NCT02519582). Although a phase I trial of Nic administered together with enzalutamide in patients with castration-resistant prostate cancer has concluded, anticipating the commencement of a phase 2 trial (NCT02532114), another phase I clinical trial is investigating the potent dose and side effects of Nic in combination with enzalutamide to treat castration-resistant prostate cancer patients (NCT03123978). A phase II clinical trial is also ongoing to evaluate the efficacy of abiraterone acetate, Nic, and prednisone in treating patients with hormone-resistant prostate cancer (NCT02807805).

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