SUCI02 inhibits the erbB-2 tyrosine kinase receptor signaling pathway and arrests the cell cycle in G1 phase in breast cancer cells.
The erbB-2 gene encodes tyrosine kinase receptor p185(neu). Overexpression of erbB-2 plays a key role in tumorigenesis and the progression of tumors such as breast cancer and ovarian cancer. Our investigation suggests that the anti-inflammatory agent N-(4-ethoxyphenol)-2-hydroxy-acid amide (SUCI02) reversibly represses tyrosine phosphorylation of erbB-2 in a dose-dependent manner, with half maximal inhibition occurring at a concentration of 21.05 micromol/L without reduced erbB-2 receptor expression. Activation of mitogen-activated protein kinase and protein kinase B, downstream molecules of the erbB-2-mediated signal transduction pathway, was inhibited following exposure to SUCI02. In contrast, tyrosine phosphorylation of epidermal growth factor receptor (EGFR) was relatively unaffected by SUCI02. Proliferation of erbB-2-overexpressing BT474 cells was inhibited to a greater extent than proliferation of EGFR-overexpressing A431 cells following exposure to SUCI02. SUCI02 induced cell cycle arrest in G(1) phase with upregulation of p27 and downregulation of pRb phosphorylation. Systemic administration of SUCI02 in nude mice resulted in inhibition of erbB-2 tyrosine kinase phosphorylation of subcutaneous human breast cancer BT474 xenografts. We conclude that SUCI02 inhibits erbB-2 tyrosine kinase phosphorylation in vitro and in vivo, shuts down the erbB-2 downstream pathway and induces cell cycle arrest in G(1) phase. These results suggest that SUCI02 is a potential novel anticancer agent that deserves further investigation. (Cancer Sci 2006; 97: 84-89).
Zhu
Xiao-Feng
XF
State Key Laboratory of Oncology in Southern China, Cancer Center, Guangzhou 510060, China.
Wang
Jing-Song
JS
Cai
Li-Ling
LL
Zeng
Yi-Xin
YX
Yang
Dajun
D
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D006880:Hydroxy Acids / Q000737:chemistry / Q000494:pharmacology*; D007399:Interphase / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D000577:Amides; D006880:Hydroxy Acids; D020928:Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C480138:N-(4-ethoyphenol)-2-hydroxy- acid amide