Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines

Andrea Cavazzoni, Roberta R. Alfieri, Caterina Carmi, Valentina Zuliani, Maricla Galetti, Claudia Fumarola, Raffaele Frazzi, Mara Bonelli, Fabrizio Bordi, Alessio Lodola, Marco Mor, Pier Giorgio Petronini

Research output: Contribution to journalArticle

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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 p21WAF1 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 μmol/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.

Original languageEnglish
Pages (from-to)361-370
Number of pages10
JournalMolecular Cancer Therapeutics
Volume7
Issue number2
DOIs
Publication statusPublished - Feb 1 2008

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Hydantoins
Lung Neoplasms
Cell Line
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Null Lymphocytes
DNA Breaks
S Phase
Non-Small Cell Lung Carcinoma
Pharmaceutical Preparations
DNA Damage
Cell Cycle
Cell Death
Adenosine Triphosphate
Binding Sites
UPR1024
Therapeutics
Growth
Proteins

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Cavazzoni, A., Alfieri, R. R., Carmi, C., Zuliani, V., Galetti, M., Fumarola, C., ... Petronini, P. G. (2008). Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines. Molecular Cancer Therapeutics, 7(2), 361-370. https://doi.org/10.1158/1535-7163.MCT-07-0477

Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines. / Cavazzoni, Andrea; Alfieri, Roberta R.; Carmi, Caterina; Zuliani, Valentina; Galetti, Maricla; Fumarola, Claudia; Frazzi, Raffaele; Bonelli, Mara; Bordi, Fabrizio; Lodola, Alessio; Mor, Marco; Petronini, Pier Giorgio.

In: Molecular Cancer Therapeutics, Vol. 7, No. 2, 01.02.2008, p. 361-370.

Research output: Contribution to journalArticle

Cavazzoni, A, Alfieri, RR, Carmi, C, Zuliani, V, Galetti, M, Fumarola, C, Frazzi, R, Bonelli, M, Bordi, F, Lodola, A, Mor, M & Petronini, PG 2008, 'Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines', Molecular Cancer Therapeutics, vol. 7, no. 2, pp. 361-370. https://doi.org/10.1158/1535-7163.MCT-07-0477
Cavazzoni, Andrea ; Alfieri, Roberta R. ; Carmi, Caterina ; Zuliani, Valentina ; Galetti, Maricla ; Fumarola, Claudia ; Frazzi, Raffaele ; Bonelli, Mara ; Bordi, Fabrizio ; Lodola, Alessio ; Mor, Marco ; Petronini, Pier Giorgio. / Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 2. pp. 361-370.
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