Ivermectin has New Application in Inhibiting Colorectal Cancer Cell Growth

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide and still lacks effective therapy. Ivermectin, an antiparasitic drug, has been shown to possess anti-inflammation, anti-virus, and antitumor properties. However, whether ivermectin affects CRC is still unclear. The objective of this study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116. We used CCK-8 assay to determine the cell viability, used an optical microscope to measure cell morphology, used Annexin V-FITC/7-AAD kit to determine cell apoptosis, used Caspase 3/7 Activity Apoptosis Assay Kit to evaluate Caspase 3/7 activity, used Western blot to determine apoptosis-associated protein expression, and used flow cytometry and fluorescence microscope to determine the reactive oxygen species (ROS) levels and cell cycle. The results demonstrated that ivermectin dose-dependently inhibited colorectal cancer SW480 and SW1116 cell growth, followed by promoting cell apoptosis and increasing Caspase-3/7 activity. Besides, ivermectin upregulated the expression of proapoptotic proteins Bax and cleaved PARP and downregulated antiapoptotic protein Bcl-2. Mechanism analysis showed that ivermectin promoted both total and mitochondrial ROS production in a dose-dependent manner, which could be eliminated by administering N-acetyl-l-cysteine (NAC) in CRC cells. Following NAC treatment, the inhibition of cell growth induced by ivermectin was reversed. Finally, ivermectin at low doses (2.5 and 5 µM) induced CRC cell arrest. Overall, ivermectin suppressed cell proliferation by promoting ROS-mediated mitochondrial apoptosis pathway and inducing S phase arrest in CRC cells, suggesting that ivermectin might be a new potential anticancer drug therapy for human colorectal cancer and other cancers.

Ivermectin induces cell cycle arrest and caspase-dependent apoptosis in human urothelial carcinoma cells

“…1). This finding is consistent with that of previous studies 5 - 7 . Notably, a previous study demonstrated that low ivermectin concentrations had no cytotoxic effect, whereas ivermectin at a concentration of ≥20 μM slightly inhibited the viability of normal cells after a 48 h exposure 6 .…”

“…Moreover, we demonstrated that ivermectin could induce caspase-dependent apoptosis in human UC cells. This finding is consistent with that of previous studies that used ivermectin to treat leukemia, glioblastoma, cad cervical, and colorectal cancer cells 7 , 17 , 20 - 23 . However, it could not induce cellular apoptosis in human breast cancer cells 24 , suggesting that ivermectin-induced apoptosis is not a general effect in human cancers.…”

“…Moreover, it exhibits antiviral activity against various RNA and DNA viruses [4]. In addition, ivermectin has shown anticancer activity in various human cancers, including leukemia, melanoma, esophageal squamous cell carcinoma, glioma, and breast, ovarian, and colon cancers [5][6][7]. Moreover, it has been demonstrated to inhibit tumor proliferation, metastasis, and angiogenesis in various cancer cells [8], as well as reverse drug resistance when combined with clinical chemotherapeutic agents [9].…”

Ivermectin and gemcitabine combination treatment induces apoptosis of pancreatic cancer cells via mitochondrial dysfunction

“…Oxidative stress plays a predominant role in various cancers (Arfin et al, 2021) as the excessive accumulation of ROS can induce mitochondrial dysfunction and apoptosis (Garrido et al, 2006;Zhang et al, 2016). Ivermectin promotes programmed cell death via ROS production (Tang et al, 2021;Zhou et al, 2021), and gemcitabine induces DNA damage via ROS (Wang X. et al, 2020). In renal cancer, ivermectin promotes programmed cell death via mitochondrial dysfunction caused by ROS generation (Zhu et al, 2017).…”

Moxidectin induces lethal autophagy arrest via CFTR

“…There have been con rmed the potential role of azithromycin in the treatment of CRC [6] . Ivermectin inhibits cell proliferation by promoting ROS-mediated mitochondrial apoptosis pathway and inducing S-phase arrest in CRC cells, while inhibiting breast cancer cell growth and inducing glioblastoma cell death in vitro and in vivo [7,8] .…”