Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan.
Int J Oncol. 2012 Mar;40(3):807-15. doi: 10.3892/ijo.2011.1243. Epub 2011 Oct 24.
Nitric oxide (NO) shows tumoricidal activity. We had previously reported that NO downregulates the phosphatidylinositol-3-kinase/Akt pathway, but upregulates the MEK/ERK pathway downstream of growth factor signaling. We hypothesized that NO donor and MEK inhibitor in combination synergistically inhibit the viability of cancer cells compared to either NO donor or MEK inhibitor alone. We determined the effects of S-nitrosoglutathione (GSNO, NO-donor) and U0126 (MEK inhibitor) on insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) signaling, proliferation and invasion in cancer cell lines. GSNO inhibits phosphorylation of IGF-I receptor (IGF-IR), EGF receptor (EGFR) and Akt, but upregulates ERK1/2 phosphorylation in MIAPaCa-2 and HCT-116 cells after stimulation by IGF-I and EGF. On the other hand, U0126 inhibits phosphorylation of ERK1/2, but upregulates phosphorylation of IGF-IR and EGFR in MIAPaCa-2 and HCT-116 cells. The combination of GSNO and U0126 downregulates phosphorylation of IGF-IR, EGFR, Akt and ERK1/2 after stimulation by IGF-I and EGF. GSNO as well as U0126, inhibits the proliferation of MIAPaCa-2, HCT-116, Panc-1, MCF-7, HT-29 and AGS cells in a dose-dependent manner. GSNO and U0126 in combination synergistically inhibit proliferation and invasion of cancer cells. These results indicate that the combined treatment of NO donor and MEK inhibitor may be promising in cancer therapy.
一氧化氮（NO）具有杀肿瘤活性。我们先前报道过，NO 下调磷脂酰肌醇-3-激酶/Akt 途径，但上调生长因子信号下游的 MEK/ERK 途径。我们假设与单独使用 NO 供体或 MEK 抑制剂相比，NO 供体和 MEK 抑制剂联合使用可协同抑制癌细胞的活力。我们测定了 S-亚硝基谷胱甘肽（GSNO，NO 供体）和 U0126（MEK 抑制剂）对胰岛素样生长因子-I（IGF-I）和表皮生长因子（EGF）信号、癌细胞系增殖和侵袭的影响。GSNO 抑制 IGF-I 受体（IGF-IR）、EGF 受体（EGFR）和 Akt 的磷酸化，但在 IGF-I 和 EGF 刺激后上调 MIAPaCa-2 和 HCT-116 细胞中 ERK1/2 的磷酸化。另一方面，U0126 抑制 ERK1/2 的磷酸化，但在 MIAPaCa-2 和 HCT-116 细胞中上调 IGF-IR 和 EGFR 的磷酸化。GSNO 和 U0126 的组合下调 IGF-I 和 EGF 刺激后 IGF-IR、EGFR、Akt 和 ERK1/2 的磷酸化。GSNO 以及 U0126 以剂量依赖的方式抑制 MIAPaCa-2、HCT-116、Panc-1、MCF-7、HT-29 和 AGS 细胞的增殖。GSNO 和 U0126 联合协同抑制癌细胞的增殖和侵袭。这些结果表明，NO 供体和 MEK 抑制剂的联合治疗可能在癌症治疗中有很大的前景。
