Kim Si Hyoung, Kang Jun Goo, Kim Chul Sik, Ihm Sung-Hee, Choi Moon Gi, Yoo Hyung Joon, Lee Seong Jin
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Biomed Pharmacother. 2016 Oct;83:22-32. doi: 10.1016/j.biopha.2016.06.014. Epub 2016 Jun 18.
The effec.t of BIIB021, a novel heat shock protein 90 (hsp90) inhibitor, on survival of thyroid carcinoma cells has not been evaluated. In this study, the impact of BIIB021 alone or in combination with the histone acetyltransferase inhibitor triptolide on survival of thyroid carcinoma cells was identified. In 8505C and TPC-1 thyroid carcinoma cells, BIIB021 caused cell death in conjunction with alterations in expression of hsp90 client proteins. Cotreatment of both BIIB021 and triptolide, compared with treatment of BIIB021 alone, decreased cell viability, and increased the percentage of dead cells and cytotoxic activity. All of the combination index values were lower than 1.0, suggesting synergistic activity of BIIB021 with triptolide in induction of cytotoxicity. In treatment of both BIIB021 and triptolide, compared with treatment of BIIB021 alone, the protein levels of total and phospho-p53, and cleaved caspase-3 were elevated, while those of total Akt, phospho-mTOR, phospho-4EBP1, phospho-S6K, phospho-NF-κB, survivin, X-linked inhibitor of apoptosis protein (xIAP), cellular inhibitor of apoptosis protein (cIAP) and acetyl. histone H4 were reduced. These results suggest that BIIB021 has a cytotoxic activity accompanied by regulation of hsp90 client proteins in thyroid carcinoma cells. Moreover, the synergism between BIIB021 and triptolide in induction of cytotoxicity is associated with the inhibition of PI3K/Akt/mTOR and NF-κB signal pathways, the underexpression of survivin and the activation of DNA damage response in thyroid carcinoma cells.
新型热休克蛋白90（hsp90）抑制剂BIIB021对甲状腺癌细胞存活的影响尚未得到评估。在本研究中，确定了BIIB021单独使用或与组蛋白乙酰转移酶抑制剂雷公藤内酯醇联合使用对甲状腺癌细胞存活的影响。在8505C和TPC-1甲状腺癌细胞中，BIIB021导致细胞死亡并伴有hsp90客户蛋白表达的改变。与单独使用BIIB021相比，BIIB021和雷公藤内酯醇联合处理降低了细胞活力，增加了死亡细胞百分比和细胞毒性活性。所有联合指数值均低于1.0，表明BIIB021与雷公藤内酯醇在诱导细胞毒性方面具有协同活性。与单独使用BIIB021相比，在BIIB021和雷公藤内酯醇联合处理中，总p53和磷酸化p53以及裂解的caspase-3的蛋白水平升高，而总Akt、磷酸化mTOR、磷酸化4EBP1、磷酸化S6K、磷酸化NF-κB、存活素、凋亡蛋白X连锁抑制剂（xIAP）、细胞凋亡蛋白抑制剂（cIAP）和乙酰化组蛋白H4的水平降低。这些结果表明，BIIB021具有细胞毒性活性，并伴有甲状腺癌细胞中hsp90客户蛋白的调节。此外，BIIB021与雷公藤内酯醇在诱导细胞毒性方面的协同作用与甲状腺癌细胞中PI3K/Akt/mTOR和NF-κB信号通路的抑制、存活素的低表达以及DNA损伤反应的激活有关。
