ZSTK474, a PI3K inhibitor, suppresses proliferation and sensitizes human pancreatic adenocarcinoma cells to gemcitabine.
ZSTK474, a PI3K inhibitor, suppresses proliferation and sensitizes human pancreatic adenocarcinoma cells to gemcitabine.
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DOI：
10.3892/or.2011.1503
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发表时间：
2012-01
期刊：
影响因子：
4.2
通讯作者：
Bae I
中科院分区：
文献类型：
--
作者：
Duong HQ;Kim HJ;Kang HJ;Seong YS;Bae I
磷脂酰肌醇3-激酶(PI3K)/Akt信号通路在细胞增殖和存活中起重要作用，在胰腺癌中经常被异常激活。PI3K/Akt抑制剂ZSTK474与关键的临床相关抗肿瘤药物吉西他滨(GEM)联用，在人胰腺癌移植瘤小鼠模型中的潜在抗肿瘤作用(S)已被报道(Yaguchi等，新型磷脂酰肌醇3-激酶抑制剂ZSTK474的抗肿瘤活性。《癌症杂志》98：546-556,2006)。然而，导致抗肿瘤作用的确切分子机制尚未很好地阐明。在本研究中，我们探讨了GEM联合ZSTK474降低人胰腺癌细胞系存活的分子机制。我们的研究表明，ZSTK474通过将细胞阻滞在G1期并通过诱导细胞凋亡来抑制细胞生长。ZSTK474还抑制Akt、Gsk3β和BAD的磷酸化。GEM和ZSTK474联合应用对胰腺癌细胞的瞬时(3天)和长期(14天)克隆形成实验均显示出协同抗肿瘤作用。因此，我们阐明了GEM和ZSTK474联合治疗可能导致抗肿瘤作用增强的分子机制。
Phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is important in cell proliferation and survival, and it is frequently and aberrantly activated in pancreatic adenocarcinoma. Potential anti-tumor effect(s) of ZSTK474, a PI3K/Akt inhibitor, together with a key clinically relevant anti-tumor agent, gemcitabine (GEM), have been reported in a human pancreatic cancer xenograft mouse model (Yaguchi et al., Anti-tumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 98:546-556, 2006). However, the precise molecular mechanism causing anti-tumor effects has not been well elucidated. In this study, we investigated the molecular mechanism of GEM plus ZSTK474 in reducing tumor cell survival in human pancreatic cancer cell lines. Our study showed that ZSTK474 inhibited cell growth by arresting cells at the G1 phase and by inducing apoptosis. ZSTK474 also inhibited the phosphorylation of Akt, GSK3β and BAD. The combination of GEM and ZSTK474 demonstrated synergistic anti-tumor effects on pancreatic cancer cells in both transient (3 days) and long-term (14 days) clonogenic assays. Thus, we elucidated the potential molecular mechanism leading to the enhanced anti-tumor effect when GEM and ZSTK474 are combined in treatment.
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