title: Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines.
abstract: In this study, we examined the mechanism of action of the novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor 5-benzylidene-hydantoin UPR1024, whose structure was designed to interact at the ATP-binding site of EGFR. The compound had antiproliferative and proapoptotic effects when tested on the non-small cell lung cancer cell line A549. The growth inhibitory effect was associated with an accumulation of the cells in the S phase of the cell cycle. Moreover, UPR1024 induced significant level of DNA strand breaks associated with increased expression of p53 and p21(WAF1) proteins, suggesting an additive mechanism of action. The presence of wild-type p53 improved the drug efficacy, although the effect was also detectable in p53 null cells. We also noted apoptotic cell death after treatment with UPR1024 at concentrations above 10 mumol/L for >24 h, with involvement of both the extrinsic and intrinsic pathways. The present data show that UPR1024 may be considered a combi-molecule capable of both blocking EGFR tyrosine kinase activity and inducing genomic DNA damage. UPR1024 or its derivatives might serve as a basis for development of drugs for the treatment of lung cancer in patients resistant to classic tyrosine kinase inhibitors.
authors.affiliation: Department of Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
authors.forename: Caterina
authors.initials: C
authors.lastname: Carmi
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuliani
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Fumarola
authors.forename: Raffaele
authors.initials: R
authors.lastname: Frazzi
authors.forename: Mara
authors.initials: M
authors.lastname: Bonelli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bordi
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D008954:Models, Biological; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D006827:Hydantoins; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; C528478:UPR1024; C031427:5-benzylhydantoin; D066246:ErbB Receptors; D000077156:Gefitinib