Division of Hematology/Oncology, Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju 54907, Korea.
Research Institute of Clinical Medicine, Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea.
Int J Mol Sci. 2021 May 31;22(11):5955. doi: 10.3390/ijms22115955.
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Histone deacetylase (HDAC) inhibitors are a new class of cytostatic agents available for the treatment of various cancers and diseases. Although numerous clinical and pre-clinical trials on the anticancer effects of panobinostat have been conducted, only a few reports have investigated its efficacy in gastric cancer. The present study aimed to investigate the effects of panobinostat in gastric cancer cells. Panobinostat significantly inhibited the cell viability and proliferation of the gastric cancer cell lines SNU484 and SNU638 in a dose-dependent manner; it reduced the colony-forming ability of these cells. Moreover, it induced apoptosis as indicated by increased protein levels of cleaved poly ADP-ribose polymerase and cleaved caspase-3. Panobinostat induced the G2/M cell cycle arrest in SNU484 and SNU638 cells and subsequently decreased the G2/M phase regulatory-associated protein expression of p-Wee1, Myt1, and Cdc2. Furthermore, panobinostat significantly inhibited the metastasis of SNU484 and SNU638 cells by regulating the expression of MMP-9 and E-cadherin. Further, it decreased the protein levels of p-Akt and forkhead box protein M1 (FOXM1). These effects were reversed by the Akt agonist SC79 and were accelerated by the Akt inhibitor LY2940002. Moreover, tumor growth in xenograft animal experiments was suppressed by panobinostat. These results indicated that panobinostat inhibits the proliferation, metastasis, and cell cycle progression of gastric cancer cells by promoting apoptosis and inactivating Akt/FOXM1 signaling. Cumulatively, our present study suggests that panobinostat is a potential drug for the treatment of gastric cancer.
胃癌是全球第五大常见癌症，也是癌症相关死亡的第三大主要原因。组蛋白去乙酰化酶（HDAC）抑制剂是一类新型的细胞生长抑制剂，可用于治疗各种癌症和疾病。尽管已经进行了大量关于帕比司他的抗癌作用的临床和临床前试验，但只有少数报告研究了其在胃癌中的疗效。本研究旨在探讨帕比司他对胃癌细胞的影响。帕比司他显著抑制胃癌细胞系 SNU484 和 SNU638 的细胞活力和增殖，呈剂量依赖性；它降低了这些细胞的集落形成能力。此外，它诱导细胞凋亡，表现为多聚 ADP-核糖聚合酶裂解和半胱天冬酶-3 裂解蛋白水平升高。帕比司他诱导 SNU484 和 SNU638 细胞 G2/M 细胞周期停滞，随后降低 G2/M 期调节相关蛋白 p-Wee1、Myt1 和 Cdc2 的表达。此外，帕比司他通过调节 MMP-9 和 E-钙粘蛋白的表达显著抑制 SNU484 和 SNU638 细胞的转移。此外，它降低了 Akt 激动剂 SC79 逆转和 Akt 抑制剂 LY2940002 加速的 p-Akt 和叉头框蛋白 M1（FOXM1）的蛋白水平。此外，在异种移植动物实验中，肿瘤生长受到帕比司他的抑制。这些结果表明，帕比司他通过促进细胞凋亡和失活 Akt/FOXM1 信号通路来抑制胃癌细胞的增殖、转移和细胞周期进程。综上所述，我们的研究表明帕比司他是治疗胃癌的一种潜在药物。
