The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of papillary thyroid cancer. While rapamycin has been shown to exhibit anti-tumor effects, it may also activate AKT, resulting in increased cell survival and drug resistance, thereby limiting its anti-tumor effects. Resveratrol can also inhibit tumor growth by regulating the PI3K/AKT/mTOR signaling pathway. The present study investigated the anti-tumor effects of the combined use of rapamycin and resveratrol in papillary thyroid cancer. We first treated two human papillary thyroid cancer cell lines (KTC-1 and TPC-1) with single or combined administration, and examined the effects on proliferation, the cell cycle, apoptosis, and invasion/migration of papillary thyroid cancer cells. A mouse xenograft model was induced with KTC-1 and TPC-1 cells followed by treatment with single or combined administration. Body weight and tumor size were monitored to assess the toxicity of each compound. The phosphorylation of AKT and the mTORC1 target p70S6 kinase (p70S6K) in tumors was also examined. Both rapamycin and resveratrol inhibited proliferation, altered the cell cycle, and induced apoptosis of papillary thyroid cancer cells. Invasion and migration were also reduced, as was the tumor growth rate in the xenograft model. Co-administration significantly enhanced the anti-tumor effects than use of any one drug, and significantly reduced the phosphorylation of AKT and p70S6K compared to treatment with rapamycin alone. Overall, compared to single use of rapamycin or resveratrol, co-administration had a synergistic effect in inhibiting proliferation and invasion/migration of papillary thyroid cancer cells and inducing apoptosis. Resveratrol is sensitizing the anti-tumor effects of rapamycin and the PI3K/AKT/mTOR signaling is involved. Although further animal and clinical studies are needed to clarify the mechanism and assess drug safety, the present study suggests that the combination of rapamycin and resveratrol may be a promising strategy for the treatment of papillary thyroid cancer.

磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）/哺乳动物雷帕霉素靶标（mTOR）信号通路在甲状腺乳头状癌的发展中起着重要作用。尽管雷帕霉素已显示出抗肿瘤作用，但它也可能激活AKT，导致细胞存活率和耐药性增加，从而限制了其抗肿瘤作用。白藜芦醇还可以通过调节PI3K / AKT / mTOR信号通路抑制肿瘤的生长。本研究调查了雷帕霉素和白藜芦醇联合使用对甲状腺乳头状癌的抗肿瘤作用。我们首先通过单次或联合治疗两种人类乳头状甲状腺癌细胞系（KTC-1和TPC-1），并研究了其对乳头状甲状腺癌细胞的增殖，细胞周期，凋亡和侵袭/迁移的影响。用KTC-1和TPC-1细胞诱导小鼠异种移植模型，然后单次或联合给药治疗。监测体重和肿瘤大小以评估每种化合物的毒性。还检查了肿瘤中AKT和mTORC1目标p70S6激酶（p70S6K）的磷酸化。雷帕霉素和白藜芦醇均抑制增殖，改变细胞周期，并诱导甲状腺乳头状癌细胞的凋亡。入侵和迁移也减少了，异种移植模型中的肿瘤生长速度也降低了。与单独使用雷帕霉素治疗相比，共同给药显着增强了抗肿瘤作用，并且显着降低了AKT和p70S6K的磷酸化。总体而言，与雷帕霉素或白藜芦醇的单次使用相比，共同给药在抑制甲状腺乳头状癌细胞的增殖和侵袭/迁移以及诱导细胞凋亡方面具有协同作用。白藜芦醇正在使雷帕霉素具有抗肿瘤作用，并且涉及PI3K / AKT / mTOR信号传导。尽管需要进一步的动物和临床研究来阐明其机理并评估药物安全性，但本研究表明雷帕霉素和白藜芦醇的组合可能是治疗甲状腺乳头状癌的一种有前途的策略。