Repositioning of Antiparasitic Drugs for Tumor Treatment

Abstract

Drug repositioning is a strategy for identifying new antitumor drugs; this strategy allows existing and approved clinical drugs to be innovatively repurposed to treat tumors. Based on the similarities between parasitic diseases and cancer, recent studies aimed to investigate the efficacy of existing antiparasitic drugs in cancer. In this review, we selected two antihelminthic drugs (macrolides and benzimidazoles) and two antiprotozoal drugs (artemisinin and its derivatives, and quinolines) and summarized the research progresses made to date on the role of these drugs in cancer. Overall, these drugs regulate tumor growth via multiple targets, pathways, and modes of action. These antiparasitic drugs are good candidates for comprehensive, in-depth analyses of tumor occurrence and development. In-depth studies may improve the current tumor diagnoses and treatment regimens. However, for clinical application, current investigations are still insufficient, warranting more comprehensive analyses.

Keywords: antiparasitic drugs; artemisinin; autophagy; benzimidazoles; drug repositioning; ferroptosis; macrolides; quinolines.

Figure 1

Efficacy of macrolide antiparasitic drugs in cancer. Apoptosis is the chief mechanism used by macrolide drugs to kill cancer cells. Macrolides trigger apoptosis through the (1) mitochondrial pathway, (2) cell cycle arrest, and (3) inhibition of the current of Ca²⁺ ion-activated Cl^- channels. Other than apoptosis, macrolides can cause autophagic death of cancer cells by (4) degrading PAK1. When used for cancer cells, macrolides show selectivity for CSCs by (5) inhibiting stem cell genes and inactivating PAK1. Macrolides also reverse the abnormal epigenetics of tumor cells through (6) the combination of PAH2 and SID domain. By binding to the extracellular segment of EGFR, macrolides can (7) inhibit the transcription of P-gp, thereby reversing tumor resistance in which MDR and MASTA1 are also involved.

Figure 2

Efficacy of benzimidazole antiparasitic drugs in cancer. Benzimidazoles can cause energy metabolism disorders and reduce cancer cell tolerance to hypoxic environments by (1) inhibiting the expression of HIF-1α and (2) inhibiting sugar intake through the GLUT/AMPK/P53 pathway. Apart from sugar metabolism, benzimidazoles also induce apoptosis by (3) inhibiting microtubule polymerization and (4) ER stress, and (5) promoting MAPK phosphorylation. By affecting numerous autophagy-related proteins (LC3, P62, and EVA1A) and downstream signals related to STAT3, benzimidazole can also cause (6) autophagic cancer cell death. (7) Benzimidazoles reduce the expression of PD-1 and (8) inhibit the accumulation of MDSC in the TME to stimulate antitumor immunity.

Figure 3

Efficacy of ARTs in cancer. With the help of endogenous peroxides, ARTs can cause oxidative stress by (1) increasing the concentration of ROS, (2) DNA damage, and (3) cell cycle arrest to cause cancer cell death. In addition to the common types of cell death, ARTs increase the concentration of unstable iron ions in cancer cells by (4) regulating a variety of iron-related proteins and IRP1/IRP2, thereby triggering ferroptosis. ARTs strengthen the cancer-killing effect of NK cells by (5) enhancing their degranulation ability and increasing the connection between NK cells and cancer cells. ARTs (6) reduce negative regulation factors (Treg cells and MDSCs) and increase IL-4 and IFN-γ in TME to stimulate T cell immune response.

Figure 4

Efficacy of quinoline antiparasitic drugs in cancer. Lysosomes are an important target of quinoline drugs, and quinolines increase the pH of the lysosome, thereby triggering a variety of cascade reactions. Quinolines can (1) inhibit the degradation of autophagy proteins to block autophagy and (2) stimulate antitumor immune responses by increasing tumor antigens. Mitochondria are also a target for quinolines. Quinolines increase the oxygen concentration in cancer cells by (3) inhibiting the related processes of mitochondrial complex III and cause apoptosis by (4) inducing oxidative stress with the change in mitochondrial membrane potential, (5) inhibiting the phosphorylation level of STAT3 in mitochondria, and (6) introducing double-strand breaks in DNA in cancer cells. (7) Quinolines inhibit the drug delivery mediated by P-gp and BRCP.