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

Hu, Li-Peng ; Huang, Wuqing LU orcid ; Wang, Xu ; Xu, Chunjie ; Qin, Wei-Ting ; Li, Dongxue ; Tian, Guangang ; Li, Qing ; Zhou, Yaoqi and Chen, Suyuan , et al. (2022) In Molecular Therapy 30(10). p.3284-3299
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Therapy
volume
30
issue
10
pages
3284 - 3299
publisher
Nature Publishing Group
external identifiers
  • scopus:85133811985
  • pmid:35765243
ISSN
1525-0024
DOI
10.1016/j.ymthe.2022.06.015
language
English
LU publication?
yes
additional info
Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
id
652224dc-6f22-4bb4-9ed8-b434f0e34095
date added to LUP
2022-06-30 10:08:19
date last changed
2024-05-16 15:04:57
@article{652224dc-6f22-4bb4-9ed8-b434f0e34095,
  abstract     = {{<p>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.</p>}},
  author       = {{Hu, Li-Peng and Huang, Wuqing and Wang, Xu and Xu, Chunjie and Qin, Wei-Ting and Li, Dongxue and Tian, Guangang and Li, Qing and Zhou, Yaoqi and Chen, Suyuan and Nie, Hui-Zhen and Hao, Yujun and Song, Jian and Zhang, Xue-Li and Sundquist, Jan and Sundquist, Kristina and Li, Jun and Jiang, Shu-Heng and Zhang, Zhi-Gang and Ji, Jianguang}},
  issn         = {{1525-0024}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{10}},
  pages        = {{3284--3299}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Molecular Therapy}},
  title        = {{Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression}},
  url          = {{http://dx.doi.org/10.1016/j.ymthe.2022.06.015}},
  doi          = {{10.1016/j.ymthe.2022.06.015}},
  volume       = {{30}},
  year         = {{2022}},
}