Mitogen-activated protein kinase routes as targets in the action of diaza-anthracene compounds with a potent growth-inhibitory effect on cancer cells.
1,8-Diaza-anthracene-tetraones are novel intermediates in the synthesis of the antifolate antibiotic diazaquinomycin A that was found before to have potent antitumor activity. Three of them (CV65, CV66, and CV70) were found to inhibit growth of a panel of several human tumor cell lines. The IC50s ranged from 0.05 to 1.5 microM and are comparable with that of doxorubicin. Among the three drugs, CV70 showed the highest cytotoxic activity. The growth-inhibitory action of these compounds was unrelated to the p53 status of the cells. At micromolar concentrations, all three compounds induced apoptosis, CV70 being the most proapoptotic. The incubation of HeLa cells with CV65, CV66, and CV70, at concentrations between 10 and 20 microM, inhibited the activation of c-Jun NH2-terminal kinase by various stimuli and prevented growth factor-induced extracellular signal-regulated kinase (ERK) 5 activation. At least one drug, CV65, also inhibited p38. This was surprising because proapoptotic antitumor drugs activate stress signaling pathways. Activation of ERK1/ 2 by growth factors or phorbol esters was unaffected by preincubation of cells with CV compounds. In vitro, CV compounds inhibit the enzyme quinone reductase but not c-Jun NH2-terminal kinase or ERK5. Because doxorubicin also inhibits quinone reductase, we conclude that the inhibitory effect of CV compounds on stress signaling kinases is not a direct effect on the kinases and is likely attributable to upstream elements of the activation cascades.
Pipaón
Carlos
C
Departamento de Biología Molecular, Facultad de Medicina, Universidad de Cantabria, Unidad Asociada al CIB-CSIC, 39011 Santander, Spain.
Gutierrez
Pilar
P
Montero
Juan Carlos
JC
Lorenzo
Mariluz
M
Eguiraun
Ana
A
De la Fuente
Jesús A
JA
Pandiella
Atanasio
A
León
Javier
J
Ortiz
José M
JM
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D048031:JNK Mitogen-Activated Protein Kinases; D020014:K562 Cells; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008956:Models, Chemical; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D015363:Quinolones / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000873:Anthracenes; C472784:CV 65 compound; C472785:CV 66 compound; C472786:CV 70 compound; D004791:Enzyme Inhibitors; D015363:Quinolones; D004317:Doxorubicin; D016660:NAD(P)H Dehydrogenase (Quinone); D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases