The development of chemo-resistance in nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge, and its underlying mechanisms remain poorly understood. In our previous studies, we highlighted the association between isoprenylcysteine carboxylmethyltransferase (ICMT) and chemoresistance in NPC. In this current research, we revealed that both 5-FU and cisplatin-resistant NPC cells exhibited elevated mitochondrial function and increased expression of mitochondrial genes, independent of ICMT. Our investigations further showed that classic mitochondrial inhibitors, such as oligomycin, antimycin, and rotenone, were notably more effective in reducing viability in chemo-resistant NPC cells compared to parental cells. Moreover, we identified two antimicrobial drugs, tigecycline and atovaquone, recognized as mitochondrial inhibitors, as potent agents for decreasing chemo-resistant NPC cells by targeting mitochondrial respiration. Remarkably, tigecycline and atovaquone, administered at tolerable doses, inhibited chemo-resistant NPC growth in mouse models and extended overall survival rates. This work unveils the efficacy of mitochondrial inhibition as a promising strategy to overcome chemo-resistance in NPC. Additionally, our findings highlight the potential repurposing of clinically available drugs like tigecycline and atovaquone for treating NPC patients who develop chemoresistance.

中文翻译：

---

批准的药物抑制线粒体功能克服了鼻咽癌的化疗耐药性。

鼻咽癌（NPC）化疗耐药的发展提出了重大的治疗挑战，其潜在机制仍知之甚少。在我们之前的研究中，我们强调了异戊二烯半胱氨酸羧甲基转移酶（ICMT）与鼻咽癌化疗耐药之间的关联。在当前的研究中，我们发现 5-FU 和顺铂耐药的 NPC 细胞均表现出线粒体功能升高和线粒体基因表达增加，且与 ICMT 无关。我们的研究进一步表明，与亲本细胞相比，经典的线粒体抑制剂，例如寡霉素、抗霉素和鱼藤酮，在降低化疗耐药性鼻咽癌细胞的活力方面明显更有效。此外，我们还发现了两种被认为是线粒体抑制剂的抗菌药物替加环素和阿托伐醌，它们是通过靶向线粒体呼吸来减少化疗耐药性鼻咽癌细胞的有效药物。值得注意的是，以可耐受剂量给药的替加环素和阿托伐醌可抑制小鼠模型中化疗耐药性鼻咽癌的生长，并延长总体存活率。这项工作揭示了线粒体抑制作为克服鼻咽癌化疗耐药性的一种有前途的策略的功效。此外，我们的研究结果强调了替加环素和阿托伐醌等临床可用药物可能重新用于治疗出现化疗耐药的鼻咽癌患者。