Progress in Redirecting Antiparasitic Drugs for Cancer Treatment

Abstract

Drug repurposing is a feasible strategy in developing novel medications. Regarding the cancer field, scientists are continuously making efforts to redirect conventional drugs into cancer treatment. This approach aims at exploring new applications in the existing agents. Antiparasitic medications, including artemisinin derivatives (ARTs), quinine-related compounds, niclosamide, ivermectin, albendazole derivatives, nitazoxanide and pyrimethamine, have been deeply investigated and widely applied in treating various parasitic diseases for a long time. Generally, their pharmacokinetic and pharmacodynamic properties are well understood, while the side effects are roughly acceptable. Scientists noticed that some of these agents have anticancer potentials and explored the underlying mechanisms to achieve drug repurposing. Recent studies show that these agents inhibit cancer progression via multiple interesting ways, inducing ferroptosis induction, autophagy regulation, mitochondrial disturbance, immunoregulation, and metabolic disruption. In this review, we summarize the recent advancement in uncovering antiparasitic drugs’ anticancer properties from the perspective of their pharmacological targets. Instead of paying attention to the previously discovered mechanisms, we focus more on newly emerging ones that are worth noticing. While most investigations are focusing on the mechanisms of their antiparasitic effect, more in vivo exploration in clinical trials in the future is necessary. Moreover, we also paid attention to what limits the clinical application of these agents. For some of these agents like ARTs and niclosamide, drug modification, novel delivery system invention, or drug combination are strongly recommended for future exploration.

Keywords:

• ferroptosis
• autophagy
• mitochondria
• immunoregulation
• glycolysis

Acknowledgments

We appreciate Ms. Nicole S. Li of the University of Illinois for her help in improving the language of the manuscript. This work was supported by National Key R&D Program of China (No.2020YFC1200100), the Guangdong Natural Science Foundation (No. 2019A1515010583) and the National Natural Science Foundation of China (No.81641094) to XL, and Fundamental Research Funds for the Central Universities (No. 20ykpy158) to YW.

Abbreviations

ARTs, artemisinin derivatives; ART, artemisinin; ROS, reactive oxygen species; IRP, iron regulatory proteins; IRE, iron responsive element; ARS, artesunate; DHA, dihydroartemisinin; GSH, glutathione; GPX4, glutathione peroxidase 4; GS-SG, oxidized glutathione; Bcl-2, B-cell lymphoma 2; DSB, double-strand break; LC3-II, Microtubule-associated protein light chain 3-II; DAPK1, death-associated protein kinase 1; mTOR, mammalian target of the rapamycin; ATG7, autophagy related 7; ATG5, autophagy related 5; TRF2, TBP-related factor 2; Atg4b, autophagy-related 4B; TFEB, transcription factor EB; JNK, Jun N-terminal protein kinase; JNK/STAT3, pathway; EVA1A, Eva-1 homolog A; ATG16L1, Autophagy Related 16 Like 1; CQ, chloroquine; PPT-1, palmitoyl-protein thioesterase 1; HCQ, hydroxychloroquine; MQ, mefloquine; LAMP1/2, lysosomal-associated membrane protein 1/2; CAF, cancer-associated fibroblasts; HNSCC, head and neck squamous cell carcinoma; TNBC, triple-negative breast cancer; MMP, matrix metalloproteinase; ATP, adenosine triphosphate; Bax, BCL (B Cell Lymphoma)-Associated X; MDSCs, myeloid-derived suppressor cells; ERK1/2, extracellular signal-regulated kinases 1 and 2; DC, dendritic cell; 5-FU, 5-Fluorouracil; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; CEA, carcinoembryonic antigen; CML, chronic myeloid leukemia; ULBP4, UL16 Binding Protein 4; NKG2D, receptor natural killer group 2D; CUR, curcumin; FoxP3, forkhead box P3; HIF-1a, hypoxia-inducible factor 1a; DAMP, damage-associated molecular pattern; TGF-b, transforming growth factor-β; NSCLC, non-small cell lung carcinoma; GLUT1, glucose transporter type 1; LNCaP, lymph node carcinoma of the prostate; G6P, glucose-6-phosphate.

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Disclosure

The authors report no conflicts of interest in this work.