Department of Gastric and Colorectal Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China.
Department of Ophthalmology, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China.
Int J Mol Med. 2018 May;41(5):2473-2484. doi: 10.3892/ijmm.2018.3460. Epub 2018 Feb 6.
PD0332991 (palbociclib/Ibrance®) is a cyclin-dependent kinase (CDK)4/6 inhibitor that has recently been approved for the treatment of estrogen receptor‑positive advanced breast cancer. The present study investigated the antiproliferative effects of PD0332991 on gastric cancer (GC) cells and the underlying molecular mechanisms. The activity of PD0332991 was tested in several GC cell lines, including AGS, KATO‑Ⅲ, NCI‑N87 and HS746T. Growth inhibitory activity of PD0332991, alone or in combination with fluorouracil (5‑FU), was measured by MTT assay. The effects of PD0332991 on cell cycle progression were analyzed by flow cytometry and western blotting. Protein pathway array and Ingenuity Pathway Analysis were used to identify signaling pathways that may mediate the antiproliferative effects of PD0332991. PD0332991 inhibited proliferation in a dose‑dependent manner and enhanced the activity of 5‑FU in all GC cell lines tested. Cells treated with PD0332991 exhibited cell cycle arrest in G1 phase of the cell cycle, whereas the number of cells in G2/M phase was decreased. PD0332991 also inhibited CDK6‑specific phosphorylation of retinoblastoma on Ser780, reduced the expression of cyclin D1, and induced expression of p53 and p27. Furthermore, 31 proteins were identified, the expression of which was significantly altered following treatment with PD0332991 in at least three cell lines. Pathway analysis indicated that the altered proteins were frequently associated with cell death, cell cycle and the molecular mechanism of cancer. The results of the present study indicated that PD0332991 may inhibit cell proliferation via modulation of the cell cycle, and may affect numerous oncogenic signaling pathways. Therefore, PD0332991 may be considered effective for the treatment of GC.
PD0332991（帕博西尼/爱博新）是一种细胞周期蛋白依赖性激酶（CDK）4/6 抑制剂，最近已被批准用于治疗雌激素受体阳性的晚期乳腺癌。本研究旨在探讨 PD0332991 对胃癌（GC）细胞的增殖抑制作用及其潜在的分子机制。在几种 GC 细胞系（AGS、KATO-Ⅲ、NCI-N87 和 HS746T）中检测 PD0332991 的活性。通过 MTT 法测定 PD0332991 单独或与氟尿嘧啶（5-FU）联合应用的生长抑制活性。通过流式细胞术和 Western blot 分析 PD0332991 对细胞周期进程的影响。蛋白通路阵列和 Ingenuity 通路分析用于鉴定可能介导 PD0332991 增殖抑制作用的信号通路。PD0332991 呈剂量依赖性抑制增殖，并增强了所有测试的 GC 细胞系中 5-FU 的活性。用 PD0332991 处理的细胞表现出细胞周期停滞在细胞周期的 G1 期，而 G2/M 期的细胞数量减少。PD0332991 还抑制视网膜母细胞瘤丝氨酸 780 上 CDK6 特异性磷酸化，降低 cyclin D1 的表达，并诱导 p53 和 p27 的表达。此外，在至少三种细胞系中，用 PD0332991 处理后，有 31 种蛋白质的表达明显改变。通路分析表明，改变的蛋白质通常与细胞死亡、细胞周期和癌症的分子机制有关。本研究结果表明，PD0332991 可能通过调节细胞周期抑制细胞增殖，并可能影响许多致癌信号通路。因此，PD0332991 可被视为治疗 GC 的有效药物。
