2,3,6-Trisubstituted quinoxaline derivative, a small molecule inhibitor of the Wnt/beta-catenin signaling pathway, suppresses cell proliferation and enhances radiosensitivity in A549/Wnt2 cells.
GDK-100017, a 2,3,6-trisubstituted quinoxaline derivative, reduced β-catenin-T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and inhibited cell proliferation in a dose-dependent manner with an IC₅₀ value of about 10 μM in A549/Wnt2 cells. GDK-100017 down-regulated the expression of Wnt/β-catenin pathway target genes such as cyclin D1 and Dkk1 but not c-myc or survivin. GDK-100017 inhibited cell proliferation by arresting the cell cycle in the G1 phase not only in A549/wnt2 cells but also in SW480 colon cancer cells. In addition to its wnt signaling inhibitory properties, GDK-100017 also enhanced the radiosensitivity of the A549 human NSCLC line. These results suggest that GDK-100017 possesses potential anti-cancer activity by inhibiting the Wnt/β-catenin signal pathway, blocking the β-catenin-TCF/LEF interaction, and enhancing radiosensitivity.
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
Sang Bum
SB
Lee
Young-Dae
YD
Gong
Young In
YI
Park
Mi-Sook
MS
Dong
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C580961:GDK-100017; D011810:Quinoxalines; D011838:Radiation-Sensitizing Agents; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1