NO donor and MEK inhibitor synergistically inhibit proliferation and             invasion of cancer cells.
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.
Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan.
Satoshi
S
Furuhashi
Hiroki
H
Sugita
Hiroshi
H
Takamori
Kei
K
Horino
Osamu
O
Nakahara
Hirohisa
H
Okabe
Keisuke
K
Miyake
Hiroshi
H
Tanaka
Toru
T
Beppu
Hideo
H
Baba
D002070:Butadienes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D002070:Butadienes; D020030:Nitric Oxide Donors; D009570:Nitriles; C113580:U 0126; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases