Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression
Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression
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特比萘芬通过诱导 dNTP 饥饿和减少免疫抑制来预防结直肠癌的生长。
DOI：
10.1016/j.ymthe.2022.06.015
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发表时间：
2022-10-05
影响因子：
12.4
通讯作者：
Ji, Jianguang
中科院分区：
文献类型：
--
作者：
Hu, Li-Peng;Huang, Wuqing;Ji, Jianguang
现有证据表明，肠道真菌的失调可能在结直肠癌的发病机制中起关键作用。我们试图探讨批准的抗真菌药物特比奈芬能否逆转真菌菌群失调，从而抑制结直肠癌的发生发展。瑞典的一项以人群为基础的研究确认了185名在确诊为结直肠癌后接受特比奈芬治疗的患者，发现与没有使用特比奈芬的患者相比，他们的死亡风险(风险比=0.50)和转移风险(风险比=0.44)都降低了。在多种结直肠癌小鼠模型中，特比奈芬的给药降低了真菌负荷、真菌诱导的髓系来源的抑制细胞(MDSC)的扩张和肿瘤负荷。未经特比奈芬治疗的小鼠粪便微生物区系移植逆转了MDSC的侵袭，部分恢复了肿瘤的增殖。机制上，特比奈芬通过降低烟酰胺腺嘌呤二核苷酸磷酸(NADP+)与还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)的比率，抑制葡萄糖-6-磷酸脱氢酶(G6PD)的活性，导致核苷酸合成中断、脱氧核糖核苷酸(DNTP)饥饿和细胞周期停滞，直接损害肿瘤细胞的增殖。综上所述，特比奈芬通过逆转真菌菌群失调、抑制肿瘤细胞增殖、抑制真菌诱导的MDSC侵袭和恢复抗肿瘤免疫反应来抑制结直肠癌的发生。
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 ter-binafine, an approved antifungal drug, might inhibit the devel-opment of CRC. A population-based study from Sweden iden-tified 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 administra-tion. In multiple mouse models of CRC, administration of ter-binafine 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 phos-phate (NADP+) to reduced form of nicotinamide adenine dinu-cleotide 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 infiltra-tion, and restoring antitumor immune response.