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Cell Death Dis. 2018 Oct 9;9(10):1032. doi: 10.1038/s41419-018-1058-z.

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

Wang X1,2,3, Shen C1,2,3, Liu Z1,2,3, Peng F1,2,3, Chen X1,2,3, Yang G1,2,3, Zhang D1,2,3, Yin Z1,2,3, Ma J4, Zheng Z1,2,3, Zhao B1,2,3, Liu H1,2,3, Wang L1,2,3, Wu J1,2,3, Han D1,2,3, Wang K1,2,3, Zhong C1,2,3, Hou X1,2,3, Zhao W1,2,3, Shu M1,2,3, Wang X1,2,3, Zhao S5,6,7.

Author information

1
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, 150001, Harbin, Heilongjiang Province, People's Republic of China.
2
Institute of Brain Science, Harbin Medical University, No. 23 Youzheng Street, Nangang District, 150001, Harbin, Heilongjiang Province, People's Republic of China.
3
Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, No. 23 Youzheng Street, Nangang District, 150001, Harbin, Heilongjiang Province, People's Republic of China.
4
Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy of Harbin Medical University, No. 157 Baojian Street, Nangang District, 150001, Harbin, Heilongjiang Province, People's Republic of China.
5
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, 150001, Harbin, Heilongjiang Province, People's Republic of China. guangsz@hotmail.com.
6
Institute of Brain Science, Harbin Medical University, No. 23 Youzheng Street, Nangang District, 150001, Harbin, Heilongjiang Province, People's Republic of China. guangsz@hotmail.com.
7
Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, No. 23 Youzheng Street, Nangang District, 150001, Harbin, Heilongjiang Province, People's Republic of China. guangsz@hotmail.com.

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.

PMID:
30302016
PMCID:
PMC6177448
DOI:
10.1038/s41419-018-1058-z
[Indexed for MEDLINE]
Free PMC Article

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