Modulation of survival signaling pathways and persistence of the genotoxic stress as a basis for the synergistic interaction between the atypical retinoid ST1926 and the epidermal growth factor receptor inhibitor ZD1839.
Strategies targeting apoptotic pathways may have relevance to improve the efficacy of antitumor therapy. Because synthetic atypical retinoids are potent inducers of apoptosis, there is an increasing interest in exploiting their potential in novel therapeutic approaches. In the present study, we have investigated the cellular effects of the combination of a novel atypical retinoid, ST1926, and the epidermal growth factor receptor inhibitor ZD1839. The results indicated a synergistic interaction between the two drugs associated with a dramatic enhancement of apoptotic response, up-regulation of the cell death receptor DR5, and caspase 8 activation. Other molecular events induced by the cotreatment included (a) a stabilization of the ST1926-induced genotoxic stress detected by formation of phosphorylated gamma-H2AX foci and (b) a complete inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation associated with activation of the proapoptotic protein BAD (i.e., inhibition of phosphorylation on Ser112). In addition, ZD1839 itself inhibited survival pathways by causing a partial dephosphorylation of Akt and a marked down-regulation of survivin. The role of ERK-mediated survival pathways in the cellular response to the drug combination was further supported by the counteracting effect of stimulation of survival pathways by an alternative receptor tyrosine kinase and by the use of a specific inhibitor of the ERK pathway. In conclusion, the results support that the survival pathways activated by epidermal growth factor receptor are determinants of the cell susceptibility to ST1926-induced apoptosis and lowering survival signals may increase the cellular sensitivity to the atypical retinoid. The favorable pharmacologic profiles of both ST1926 and ZD1839 suggest that the combination of these well-tolerated agents may have therapeutic potential.
Zanchi
Chiara
C
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Zuco
Valentina
V
Lanzi
Cinzia
C
Supino
Rosanna
R
Zunino
Franco
F
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D004249:DNA Damage; D004357:Drug Synergism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014846:Vulvar Neoplasms / Q000188:drug therapy / Q000473:pathology
C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D002934:Cinnamates; D011799:Quinazolines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D066246:ErbB Receptors; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; D000218:Adamantane; D000077156:Gefitinib