Department of Endocrinology, The Third People's Hospital of Guangxi Zhuang Autonomous Region, Riverside Hospital of Guangxi Zhuang Autonomous Region, Heti Road 85, Qingxiu District, Nanning, 530021, China.
J Bioenerg Biomembr. 2018 Aug;50(4):263-270. doi: 10.1007/s10863-018-9755-y. Epub 2018 Apr 23.
The clinical management of anaplastic thyroid carcinoma and follicular thyroid carcinoma is challenging and requires an alternative therapeutic strategy. Although atovaquone is an FDA-approved anti-malarial drug, studies has recently demonstrated its anti-cancer activities. In line with these efforts, our study shows that atovaquone is an attractive candidate for thyroid cancer treatment. We show that atovaquone significantly inhibits growth, migration and survival in a concentration-dependent manner in 8505C and FTC113 cells. Mechanistically, atovaquone inhibits mitochondrial complex III activity, leading to mitochondrial respiration inhibition and reduction of ATP production in thyroid cancer cells. The inhibitory effects of atovaquone is reversed in mitochondrial respiration-deficient 8505C ρ0 cells, confirming mitochondrial respiration as the mechanism of atovaquone's action in thyroid cancer. In addition, atovaquone suppresses phosphorylation of STAT3 in thyroid cancer wildype but not ρ0 cells, demonstrating that STAT3 phosphorylation inhibition by atovaquone is a consequence of mitochondrial respiration inhibition. Notably, we further demonstrate that atovaquone significantly augments doxorubicin's inhibitory effects via suppressing mitochondrial respiration and STAT3. Our findings suggest that atovaquone can be repurposed for thyroid cancer treatment. Our work also highlights that targeting mitochondrial respiration may represent potential therapeutic strategy in thyroid cancer.
间变性甲状腺癌和滤泡状甲状腺癌的临床治疗具有挑战性，需要一种替代的治疗策略。虽然阿托伐醌是一种 FDA 批准的抗疟药物，但最近的研究表明它具有抗癌活性。与这些努力一致，我们的研究表明阿托伐醌是治疗甲状腺癌的有吸引力的候选药物。我们表明，阿托伐醌以浓度依赖的方式显著抑制 8505C 和 FTC113 细胞的生长、迁移和存活。在机制上，阿托伐醌抑制线粒体复合物 III 的活性，导致甲状腺癌细胞中线粒体呼吸抑制和 ATP 产生减少。在线粒体呼吸缺陷的 8505C ρ0 细胞中，阿托伐醌的抑制作用被逆转，这证实了线粒体呼吸是阿托伐醌在甲状腺癌中作用的机制。此外，阿托伐醌抑制甲状腺癌野生型细胞中 STAT3 的磷酸化，但不能抑制 ρ0 细胞中的磷酸化，表明阿托伐醌通过抑制线粒体呼吸抑制 STAT3 的磷酸化。值得注意的是，我们进一步证明阿托伐醌通过抑制线粒体呼吸和 STAT3 显著增强多柔比星的抑制作用。我们的发现表明，阿托伐醌可被重新用于甲状腺癌的治疗。我们的工作还强调，靶向线粒体呼吸可能代表甲状腺癌的潜在治疗策略。
