Nitazoxanide, an antiprotozoal drug, inhibits late-stage autophagy and promotes ING1-induced cell cycle arrest in glioblastoma

Abstract

Glioblastoma is the most common and aggressive primary brain tumor in adults. New drug design and development is still a major challenge for glioma treatment. Increasing evidence has shown that nitazoxanide, an antiprotozoal drug, has a novel antitumor role in various tumors and exhibits multiple molecular functions, especially autophagic regulation. However, whether nitazoxanide-associated autophagy has an antineoplastic effect in glioma remains unclear. Here, we aimed to explore the underlying molecular mechanism of nitazoxanide in glioblastoma. Our results showed that nitazoxanide suppressed cell growth and induced cell cycle arrest in glioblastoma by upregulating ING1 expression with a favorable toxicity profile. Nitazoxanide inhibited autophagy through blockage of late-stage lysosome acidification, resulting in decreased cleavage of ING1. A combination with chloroquine or Torin1 enhanced or impaired the chemotherapeutic effect of nitazoxanide in glioblastoma cells. Taken together, these findings indicate that nitazoxanide as an autophagy inhibitor induces cell cycle arrest in glioblastoma via upregulated ING1 due to increased transcription and decreased post-translational degradation by late-stage autophagic inhibition.

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

“…We ଏnd that both thiazolides arrest CRC cells in the G1 phase of the cell cycle, independent of their ability to cause cell death. Although NTZ has been recently shown to induce autophagy-related cell cycle arrest in glioblastoma cell lines [28], we here demonstrate that in CRC cells thiazolideinduced G1 arrest is primarily regulated by the mTOR/c-Myc/p27 axis. Our study also revealed differences and similarities between these two compounds.…”

“…Subsequently, various high-throughput screenings conଏrmed the anticancer activity of NTZ in 2D and 3D culture systems of tumor cells. While activities of NTZ on a broad range of cellular pathways, e.g., metabolism, proliferation, and autophagy, have been reported, no clear mechanism of antitumor activity has been described so far [28][29][30][31]. Thus, further investigations are required to shed light on the antitumor activity of NTZ to fully exploit its anticancer potential.…”

Canonical and Noncanonical Autophagy as Potential Targets for COVID-19

“…Briefly, chloroquine, apart from disorganizing the Golgi, induces lysosomal alkalinization, which prevents amphisome/autophagosome-lysosome fusion and blocks the vesicle trafficking system [ 53 , 54 , 55 , 93 ], which potentially affects the replication cycle of coronavirus systemically, including their entry, which is mediated by pH-dependent endocytosis and requires a low pH for the S protein to trigger its membrane fusion activity [ 94 , 95 ]. Nitazoxanide is another late-stage autophagy blocker [ 96 ] that shows high anti-SARS-CoV-2 activity in cell cultures (IC 50 : 2.12 μM) [ 97 ], although it should be considered that its main metabolite, tizoxanide, induces autophagy by inhibiting the PI3K-AKT-MTOR pathway [ 98 ]. At this moment, the scientific community is focusing efforts in searching, by different approaches, for effective drugs against this pathogen and continuously revealing autophagy modulators [ 99 , 100 , 101 ].…”

Highlights in Resistance Mechanism Pathways for Combination Therapy

“…Several analgesics and anesthetics, and antipsychotic, antibiotic and antiprotozoal drugs, among many other classes, have already been repurposed or are being tested on an oncology setting, based on modulation of numerous cell signaling pathways commonly disrupted in cancer [185]. Nitazoxanide (NTZ) is an antiprotozoal drug, which has been recently shown to inhibit autophagy in glioblastoma cells [187]. The combination with chloroquine (CQ), a well-known antimalarial autophagy inhibitor, had a synergistic effect, with CQ sensitizing the glioma cells to NTZ.…”