Plk1 inhibition enhances the efficacy of gemcitabine in human pancreatic cancer
Plk1 inhibition enhances the efficacy of gemcitabine in human pancreatic cancer
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DOI：
10.1080/15384101.2016.1148838
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发表时间：
2016-03-03
期刊：
影响因子：
4.3
通讯作者：
Liu, Xiaoqi
中科院分区：
文献类型：
--
作者：
Li, Jie;Wang, Ruixin;Liu, Xiaoqi
吉西他滨是胰腺癌患者化疗的标准治疗，它可以直接掺入DNA或抑制核糖核苷酸还原酶，以防止DNA复制，从而防止肿瘤细胞生长。然而，大多数胰腺肿瘤对吉西他滨产生耐药性。Polo样激酶1（Plk 1）是许多细胞周期事件中的关键调节因子，在人类胰腺癌中显著升高。在这项研究中，我们表明，Plk 1是所需的G1/S转换和Plk 1的抑制显着降低人胰腺癌细胞的DNA合成率。此外，检查了特异性Plk 1抑制剂GSK 461364 A与吉西他滨的联合作用。我们发现Plk 1的抑制显著增强了吉西他滨在培养的胰腺癌细胞和Panc 1衍生的原位胰腺癌异种移植瘤中的抗肿瘤活性。总体而言，我们的研究表明，共靶向Plk 1可以显着提高吉西他滨的疗效，为吉西他滨耐药的人胰腺癌的治疗提供了一个有前途的新的治疗选择。
Gemcitabine is the standard-of-care for chemotherapy in patients with pancreatic adenocarcinoma and it can directly incorporate into DNA or inhibit ribonucleotide reductase to prevent DNA replication and, thus, tumor cell growth. Most pancreatic tumors, however, develop resistance to gemcitabine. Polo-like kinase 1 (Plk1), a critical regulator in many cell cycle events, is significantly elevated in human pancreatic cancer. In this study, we show that Plk1 is required for the G1/S transition and that inhibition of Plk1 significantly reduces the DNA synthesis rate in human pancreatic cancer cells. Furthermore, the combined effect of a specific Plk1 inhibitor GSK461364A with gemcitabine was examined. We show that inhibition of Plk1 significantly potentiates the anti-neoplastic activity of gemcitabine in both cultured pancreatic cancer cells and Panc1-derived orthotopic pancreatic cancer xenograft tumors. Overall, our study demonstrates that co-targeting Plk1 can significantly enhance the efficacy of gemcitabine, offering a promising new therapeutic option for the treatment of gemcitabine-resistant human pancreatic cancer.