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Veterinary Antiparasitic to Human Anticancer

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]

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]

in vivo

Human

H460 and A549

in vitro

nu/nu

mice

FZ

LC

microtubule disruption, p53 activation and down regulation of pivotal glycolytic enzymes

[19]

in vivo

Human

P493-6

in vitro

SCID mice

FZ

Lymphoma

Tubulin disruption

[20]

in vivo

Mice

EMT6

in vitro

BALB/c Rw mice

FZ

Mammary carcinoma

Tubulin disruption

[21]

in vivo

Human

OCI-AML-2

in vitro

SCID mice

FLU

Leukaemia and Myeloma

Tubulin disruption

[22]

in vivo

Human

MDA-MB-231, BT-549, SK-BR-3 and MCF-7

in vitro

Mice

FLU

BC

Tubulin disruption

[23]

in vivo

Human

TNBC cell lines MDA-MB-231 and MDA-MB-468

in vitro

Mice

FLU

BC

Apoptosis

[24]

in vivo

Human

BT474, SK-BR-3, MDA-MB-453, JIMT-1

in vitro

BALB/c mice

FLU

BC

Tubulin disruption

[25]

in vivo

Apoptosis

Human

HCT116, RKO and SW480

in vitro

BALB/c mice

FLU

CRC

Apoptosis

[26]

in vivo

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]

in vivo

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]

in vivo

Mouse

GL261

in vitro

C57BL6 Mice

MZ

Brain tumour

Tubulin disruption

[32]

in vivo

Apoptosis

Human

GBM U87-MG, D54, H80, H247, H392, H397, H502 and H566

in vitro

C57BL/6 mice

MZ

Brain cancer

Apoptosis

[33]

in vivo

Mouse

GL261

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]

in vivo

Murine

CP2 and SP1

in vitro

BALB/c mice

MZ

PC

Tubulin disruption

[36]

in vivo

Human

KKU-M213

in vitro

Nude mice

MZ

Bile duct

Cancer

Apoptosis

[37]

in vivo

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]

in vivo

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]

in vivo

Human

NRASQ61K

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]

in vivo

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]

in vivo

Human

MDA-MB-231

in vitro

BALB/c nude mice

Nic and cisplatin

BC

Apoptosis and inhibition of Akt, ERK, and Src pathways

[49]

in vivo

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]

in vivo

Mouse

4T1

in vitro

BALB/c mice

Nic

BC

Apoptosis and suppression of cell migration and invasion

[52]

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]

in vivo

Human

K562 and KBM5-T315I cells

in vitro

NOD mice

Nic

Chronic myelogenous leukemia

Inhibition of FOXM1/β-catenin Pathway

[54]

in vivo

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]

in vivo

Human

MCF7

in vitro

Mice

Nic

Adeno-carcinoma

Inhibition of PI3K-dependent signalling

[56]

HCC1954

Carcinoma

BT-474

in vivo

Ductal Carcinoma

MDA-MB-361 and

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]

in vivo

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]

in vivo

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

Murine

MC38

in vitro

APCmin/+ mouse

Nic-EN and oxyclozanide

CC

Mitochondrial uncoupling

[63]

in vivo

Human

HCT116

in vitro

Rodent

C2C12

in vitro

in vivo

Human

SKOV3 and CP70

in vitro

SCID mice

Nic

OC

Induction of metabolic shift to glycolysis

[64]

in vivo

Human

OVCAR-3, SKOV-3 and A2780

in vitro

NOD/

SCID mice

Nic

OC

Inhibition of CP70sps and primary OTICs

[65]

in vivo

Human

SKOV3.ip1

in vitro

Mice

Nic

OC

Inhibition of Wnt/β-catenin Pathway

[66]

in vivo

Human

SKOV3 and HO8910

in vitro

Athymic Nude mice

Nic

OC

Mitochondrial Respiration and aerobic glycolysis

[67]

in vivo

Human

A2780ip2, A2780cp20, and SKOV3Trip2

in vitro

SCID

mice

Nic

OC

Inhibition of Wnt/β-catenin, mTOR and STAT3 pathways

[68]

in vivo

Human

Tumorspheres

in vitro

Mice

Nic and its analogs in combination with carboplatin

OC

Cytotoxicity

[69]

in vivo

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]

in vivo

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]

in vivo

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]

in vivo

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]

in vivo

Human

CaLo, HeLa, SiHa, CasKi, DoTc2, ViBo and C-33A

in vitro

SCID mice

Nic

Cervical cancer

Inhibition of mTOR signaling

[82]

in vivo

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]

in vivo

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]

in vivo

Human

NCI-H295R and SW-13

in vitro

Nu+/Nu+ mice

Nic

Adrenocortical Carcinoma

Induction of G1 cell-cycle arrest mitochondrial uncoupling

[86]

in vivo

Human

A498 and Caki-1

in vitro

Athymic nude mice

Nic

Renal cell carcinoma

Inhibition of cell proliferation, migration and cell cycle progression

[87]

in vivo

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]

in vivo

Human

A431 and A375

in vitro

BALB/c nude mice

RFX

Skin cancer

Inhibition of CDK4/6

[90]

in vivo

Human

HCT-116 and HT-29

in vitro

Apcmin/+ mice

RFX

CRC

Inhibition of cell proliferation

[91]

in vivo

Human

HCT-116 and

DLD1 cells

in vitro

BALB/c nude mice

RFX

CRC

Induction of ICD of CRC cells

[92]

in vivo

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

Cancer of Unknown Origin

2

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).

This entry is adapted from 10.3390/ijms23084315

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