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Anthelmintics for Drug Repurposing: Opportunities and Challenges ⇑ ⇑ Seyed Ebrahim Alavi , Hasan Ebrahimi Shahmabadi

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Anthelmintics for Drug Repurposing: Opportunities and Challenges ⇑ ⇑ Seyed Ebrahim Alavi , Hasan Ebrahimi Shahmabadi Saudi Pharmaceutical Journal 29 (2021) 434–445 Contents lists available at ScienceDirect Saudi Pharmaceutical Journal journal homepage: www.sciencedirect.com Review Anthelmintics for drug repurposing: Opportunities and challenges ⇑ ⇑ Seyed Ebrahim Alavi , Hasan Ebrahimi Shahmabadi Department of Microbiology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran article info abstract Article history: Drug repositioning is defined as a process to identify a new application for drugs. This approach is critical Received 19 February 2021 as it takes advantage of well-known pharmacokinetics, pharmacodynamics, and toxicity profiles of the Accepted 3 April 2021 drugs; thus, the chance of their future failure decreases, and the cost of their development and the Available online 16 April 2021 required time for their approval are reduced. Anthelmintics, which are antiparasitic drugs, have recently demonstrated promising anticancer effects in vitro and in vivo. This literature review focuses on the Keywords: potential of anthelmintics for repositioning in the treatment of cancers. It also discusses their pharma- Anthelmintics cokinetics and pharmacodynamics as antiparasitic drugs, proposed anticancer mechanisms, present Antiparasitic development conditions, challenges in cancer therapy, and strategies to overcome these challenges. Cancer Ó Drug repositioning 2021 The Authors. Published by Elsevier B.V. on behalf of King Saud University. This is an open access Solubility article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction . ...................................................................................................... 435 2. Physicochemical properties of anthelmintics . ................................................................ 435 2.1. Pharmacokinetics and pharmacodynamic . ......................................................................... 435 2.1.1. Metabolism and excretion . .............................................................................. 436 3. Efficacy and spectra of activity of anthelmintics . ................................................................ 436 3.1. Benzimidazoles and pro-benzimidazoles . ......................................................................... 436 3.2. Imidazothiazoles and tetrahydropyrimidines ......................................................................... 437 3.3. Macrocyclic lactones . ......................................................................................... 437 4. Mode of action as anti-cancer agents . ................................................................................... 437 4.1. Anthelmintics under clinical trials . ......................................................................... 437 4.1.1. Albendazole. .............................................................................. 437 4.1.2. Ivermectin .............................................................................................. 437 4.1.3. Levamisole . .............................................................................. 438 4.1.4. Mebendazole. .............................................................................. 439 4.1.5. Niclosamide . .............................................................................. 439 4.2. Anthelmintics with promising anti-cancer effects . ...................................................... 439 4.2.1. Flubendazole. .............................................................................. 439 4.2.2. Rafoxanide . .............................................................................. 439 4.2.3. Nitazoxanide . .............................................................................. 439 4.2.4. Praziquantel . .............................................................................. 440 ⇑ Corresponding authors. E-mail addresses: [email protected] (S.E. Alavi), [email protected] (H. Ebrahimi Shahmabadi). Peer review under responsibility of King Saud University. Production and hosting by Elsevier https://doi.org/10.1016/j.jsps.2021.04.004 1319-0164/Ó 2021 The Authors. Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Seyed Ebrahim Alavi and H. Ebrahimi Shahmabadi Saudi Pharmaceutical Journal 29 (2021) 434–445 4.2.5. Pyrvinium pamoate . .............................................................................. 440 4.2.6. Piperazine .............................................................................................. 440 4.2.7. Eprinomectin. .............................................................................. 440 5. Challenges with anthelmintics in cancer therapy . ................................................................ 440 6. Strategies to overcome these challenges . ................................................................ 441 6.1. Nanoparticles for improving the solubility of anthelmintics . ...................................................... 441 6.2. Pro-drug formulations. ......................................................................................... 441 6.3. Production of solid dispersions . ......................................................................... 441 7. Conclusion and future perspectives . ................................................................................... 443 Funding . ...................................................................................................... 443 Declaration of Competing Interest . ................................................................................... 443 References . ...................................................................................................... 443 1. Introduction more than 270 drugs are being assessed for their potential anti- tumor activity (Armando et al., 2020), and from these, approxi- Cancer, with rapidly increasing incidence (18.1 million new mately 57% have demonstrated anti-tumor effects in human clin- cases and annual incidence of 3–5%, 2018) and mortality (9.6 mil- ical trials (Xue, Li, Xie, & Wang, 2018). One of the important lion patients, 2018), is one of the most critical health issues groups of drugs, which have demonstrated anti-tumor activity, throughout the world (Hassankhani, Rahmani, Taleghani, Sanaat, is anthelmintic agents. & Dehghannezhad, 2020; J. Zhang et al., 2019). Many efforts have Anthelmintics are a series of compounds, demonstrating anti- been made to develop anti-cancer agents, and various lead candi- infectious activity against helminths, which settle in the human dates have been developed at preclinical and clinical stages; how- intestine (Laudisi et al., 2020). These therapeutics were initially ever, only 5% of compounds that enter phase I clinical trials receive developed for the treatment of veterinary parasites and have sub- the end approval (Kato et al., 2015). sequently been used for patients, suffering from helminthiasis. Generally, to develop a novel anti-neoplastic agent, various Anthelmintics have a variety of chemical entities and function natural-based compounds derived from microorganisms, animals, through changing the parasite (worm) metabolism or paralyzing and plants are evaluated by a variety of pharmacological and bio- the parasite, in which the parasite can be eliminated by the host chemical analyses, that often continue with the whole chemical immune system (Laudisi et al., 2020; Rajagopal et al., 2019). It synthesis or modification of determined individual compounds has been demonstrated that some of the anthelmintics are able (Cˇánˇová, Rozkydalová, & Rudolf, 2017). Further, this process of to inhibit critical oncogenic pathways, such as Wnt/b-catenin, sig- drug development has been complemented by screening the nal transducer and activator of transcription proteins 3 (STAT3), assays of libraries of all recognized and determined compounds and nuclear factor kappa-light-chain-enhancer of activated B cells to select the potentially appropriate candidates for further (NF-jB) (Laudisi et al., 2020); therefore, their application for cancer assessment. However, these strategies are associated with several treatment has been considered. difficulties, such as financial burden, laboriousness, and longer This literature review provides an overview of the updated duration for drug development (Cˇánˇová et al., 2017). Currently, information about anthelmintics with anti-cancer activity and the development of a new drug takes 10–15 years, and the success their possible use as anti-cancer agents (i.e., repositioned drugs). rate is negligible (approximately 2%). As the cost of clinical trials These anthelmintics are characterized, in terms of their i) struc- has recently increased, the number of new drugs, approved by tural analysis, ii) tumor type-specific effects, iii) mode of action, Food and Drug Administration (FDA) has been decreased (Laudisi, and iv) up to date data about the clinical trials. It also discusses Marônek, Di Grazia, Monteleone, & Stolfi, 2020; Scannell, the challenges for their applications as anti-cancer agents, such Blanckley, Boldon, & Warrington, 2012). Between 2004 and 2012, as low water solubility and low bioavailability, and strategies to on average 2–3 billion US dollars were spent for a pharmaceutical overcome these challenges, such as nanocarrier-based formula- clinical trial, and considering the inflation, this value would be tions,
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