Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression

Existing evidence indicates that gut fungal dysbiosis might play a key role in the pathogenesis of colorectal cancer (CRC). We sought to explore whether reversing the fungal dysbiosis by terbinafine, an approved antifungal drug, might inhibit the development of CRC. A population-based study from Swe...

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Bibliographic Details
Published in:	Molecular therapy 2022-10, Vol.30 (10), p.3284-3299
Main Authors:	Hu, Li-Peng, Huang, Wuqing, Wang, Xu, Xu, Chunjie, Qin, Wei-Ting, Li, Dongxue, Tian, Guangang, Li, Qing, Zhou, Yaoqi, Chen, Suyuan, Nie, Hui-Zhen, Hao, Yujun, Song, Jian, Zhang, Xue-Li, Sundquist, Jan, Sundquist, Kristina, Li, Jun, Jiang, Shu-Heng, Zhang, Zhi-Gang, Ji, Jianguang
Format:	Article
Language:	eng
Subjects:	Cancer and Oncology Cancer och onkologi Clinical Medicine Klinisk medicin Medical and Health Sciences Medicin och hälsovetenskap Original
Online Access:	Get full text
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Summary:	Existing evidence indicates that gut fungal dysbiosis might play a key role in the pathogenesis of colorectal cancer (CRC). We sought to explore whether reversing the fungal dysbiosis by terbinafine, an approved antifungal drug, might inhibit the development of CRC. A population-based study from Sweden identified a total of 185 patients who received terbinafine after their CRC diagnosis and found that they had a decreased risk of death (hazard ratio = 0.50) and metastasis (hazard ratio = 0.44) compared with patients without terbinafine administration. In multiple mouse models of CRC, administration of terbinafine decreased the fungal load, the fungus-induced myeloid-derived suppressor cell (MDSC) expansion, and the tumor burden. Fecal microbiota transplantation from mice without terbinafine treatment reversed MDSC infiltration and partially restored tumor proliferation. Mechanistically, terbinafine directly impaired tumor cell proliferation by reducing the ratio of nicotinamide adenine dinucleotide phosphate (NADP + ) to reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), suppressing the activity of glucose-6-phosphate dehydrogenase (G6PD), resulting in nucleotide synthesis disruption, deoxyribonucleotide (dNTP) starvation, and cell-cycle arrest. Collectively, terbinafine can inhibit CRC by reversing fungal dysbiosis, suppressing tumor cell proliferation, inhibiting fungus-induced MDSC infiltration, and restoring antitumor immune response. Terbinafine prevents colorectal cancer (CRC) growth by inhibiting fungus-induced MDSC expansion and exerting direct cytotoxic effects on CRC cells, both of which evoke antitumor immune responses and suppress cancer cell growth.
ISSN:	1525-0016 1525-0024 1525-0024