Thiazolides promote G1 cell cycle arrest in colorectal cancer cells by targeting the mitochondrial respiratory chain

Abstract

Systemic toxicity and tumor cell resistance still limit the efଏcacy of chemotherapy in colorectal cancer. Therefore, alternative treatments are desperately needed. The thiazolide Nitazoxanide (NTZ) is an FDA-approved drug for the treatment of parasite-mediated infectious diarrhea with a favorable safety proଏle. Interestingly, NTZ and the thiazolide RM4819-its bromo-derivative lacking antibiotic activity-are also promising candidates for cancer treatment. Yet the exact anticancer mechanism(s) of these compounds still remains unclear. In this study, we systematically investigated RM4819 and NTZ in 2D and 3D colorectal cancer culture systems. Both compounds strongly inhibited proliferation of colon carcinoma cell lines by promoting G1 phase cell cycle arrest. Thiazolide-induced cell cycle arrest was independent of the p53/p21 axis, but was mediated by inhibition of protein translation via the mTOR/c-Myc/p27 pathway, likely caused by inhibition of mitochondrial respiration. While both thiazolides demonstrated mitochondrial uncoupling activity, only RM4819 inhibited the mitochondrial respiratory chain complex III. Interestingly, thiazolides also potently inhibited the growth of murine colonic tumoroids in a comparable manner with cisplatin, while in contrast to cisplatin thiazolides did not affect the growth of primary intestinal organoids. Thus, thiazolides appear to have a tumor-selective antiproliferative activity, which offers new perspectives in the treatment of colorectal cancer.

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

“…Although RM4819 (10 µM) did not show the anti-bacterial activity of NTZ, it could arrest the cell cycle and uncouple the mitochondrial respiration as NTZ did. Moreover, RM4819 strongly suppressed the activity of mitochondrial complex III, thereby inducing relevant energy deficiency in CRC cells [48]. Similar results were obtained in intestinal organoids, wherein both NTZ and RM4819 inhibited the proliferation of intestinal tumoroids, without affecting normal intestinal organoids [48].…”

“…Moreover, RM4819 strongly suppressed the activity of mitochondrial complex III, thereby inducing relevant energy deficiency in CRC cells [48]. Similar results were obtained in intestinal organoids, wherein both NTZ and RM4819 inhibited the proliferation of intestinal tumoroids, without affecting normal intestinal organoids [48]. Despite the encouraging evidence, no clinical trials are currently ongoing to test the safety and efficacy of NTZ and its derivates in CRC patients.…”

“…Nitazoxanide (NTZ) belongs to the thiazolide family and is effective against intestinal parasites (e.g., Cryptosporidium parvum and Giardia lamblia); Helicobacter and Clostridium-driven bacterial infections; and viral infections [74][75][76][77][78]. NTZ is considered a promising candidate for cancer treatment due to a large body of evidence reporting anti-proliferative and pro-apoptotic activities against different cancer types [45][46][47][48] and its excellent pharmacokinetic and safety profiles. Concerning CRC, NTZ (50 µM) was shown to induce apoptosis in CRC cells in a glutathione-S-transferase P1 (GSTP1)-dependent manner [45].…”

“…Mechanistically, NTZ (10 µM) directly targeted the peptidyl arginine deiminase 2, leading to increased citrullination and degradation of β-catenin in CRC cells [47]. More recently, Ripani and co-workers tested the anti-cancer efficacy of the nitazoxanide bromo-derivate RM4819 [48]. Although RM4819 (10 µM) did not show the anti-bacterial activity of NTZ, it could arrest the cell cycle and uncouple the mitochondrial respiration as NTZ did.…”

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

“…This interference with bioenergetic processes selectively induces cell cycle arrest, prior to Bim-mediated apoptosis in tumor cells, thus contributing to the anticancer activity of thiazolides. 53,125 In the context of metabolic transformation of tumor cells, the Warburg effect is probably the best described phenomenon. It is defined as a switch from ATP generation via mitochondrial oxidative phosphorylation to aerobic glycolysis that refers to the fermentation of glucose to lactate in the presence of oxygen.…”