ucn-1028-c and Carcinoma--Non-Small-Cell-Lung

We developed Wnt/β-catenin inhibitors by identifying 13 number of 3-arylethynyl-substituted pyrido[2,3,-b]pyrazine derivatives that were able to inhibit the Wnt/β-catenin signal pathway and cancer cell proliferation. In the optimization process, a series of 2,3,6-trisubstituted pyrido[2,3,-b]pyrazine core skeletons showed were shown to higher activity than 2,3,6-trisubstituted quinoxaline's and thus hold promise for use as potential small-molecule inhibitors of the Wnt/β-catenin signal pathway in non-small-cell lung cancer cell (NSCLC) lines. And we have studied the pharmacophore mapping for compound 954, which presented the highest activity with a fit value of 2.81. The pharmacophore mapping for the compounds including 954, pyrido[2,3,-b]pyrazine core had hydrogen-bond acceptor site and hydrophobic center roles.

Topics: Antineoplastic Agents; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Models, Molecular; Molecular Structure; Pyrazines; Pyridines; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured; Wnt Proteins

We screened 1434 small heterocyclic molecules and identified thirteen 2,3,6-trisubstituted quinoxaline derivatives that were able to inhibit the Wnt/β-catenin signal pathway and cell proliferation. In the screen, some of the hit compounds such as the ethylene group-coupled quinoxaline derivatives were shown to hold promise for use as potential small-molecule inhibitors of the Wnt/β-catenin signal pathway in non-small-cell lung cancer cell lines.

Topics: Antineoplastic Agents; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lung Neoplasms; Quinoxalines; Signal Transduction; Wnt Proteins

Amphiregulin (AR) and insulin-like growth factor-1 (IGF1) are growth factors known to promote non-small cell lung cancer (NSCLC) survival. We have previously published that 1) AR and IGF1, secreted by H358 NSCLC cells, cooperate to protect those cells and H322 NSCLC cells from serum-starved apoptosis; 2) H358 cells resist Bax-induced apoptosis through an inhibition of Bax conformational change. We show here that the antiapoptotic activity of the AR/IGF1 combination is specifically abolished by the PKC inhibitors calphostin C and staurosporine, but not by the MAPK and phosphatidylinositol 3-kinase inhibitors PD98059 and wortmannin, suggesting the involvement of a PKC-dependent and MAPK- and phosphatidylinositol 3-kinase-independent survival pathway. The PKCdelta inhibitor rottlerin restores apoptosis induced by serum deprivation. In addition, phosphorylation of PKCdelta and PKCzeta/lambda, but not of PKCalpha/beta(II), increases in serum-starved H358 cells and in H322 cells treated with an AR/IGF1 combination and is blocked by calphostin C. The combination of AR and IGF1 increases p90(rsk) and Bad phosphorylation as well as inhibiting the conformational change of Bax by a PKC-dependent mechanism. Finally, PKCdelta, PKCzeta, or p90(rsk) small interfering RNAs block the antiapoptotic activity of AR/IGF1 combination but have no effect on partial apoptosis inhibition observed with each factor used alone. Constitutively active PKC expression inhibits serum deprivation-induced apoptosis, whereas a catalytically inactive form of p90(rsk) restores it. Thus, AR and IGF1 cooperate to prevent apoptosis by activating a specific PKC-p90(rsk)-dependent pathway, which leads to Bad and Bax inactivation. This signaling pathway is different to that used by single factor.

Topics: Amphiregulin; Androstadienes; Apoptosis; bcl-2-Associated X Protein; bcl-Associated Death Protein; Carcinoma, Non-Small-Cell Lung; Carrier Proteins; Cell Line, Tumor; Culture Media, Serum-Free; EGF Family of Proteins; Enzyme Inhibitors; Flavonoids; Glycoproteins; Humans; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Isoenzymes; Lung Neoplasms; MAP Kinase Signaling System; Models, Biological; Naphthalenes; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase C; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Staurosporine; Wortmannin