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|Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model|
|Authors: ||Diaz, R. (Ramón)|
Nguewa, P. (Paul Alain)
Parrondo, R. (Ricardo)
Perez-Stable, C. (Carlos)
Manrique, I. (Irene)
Redrado, M. (Miriam)
Catena, R. (R.)
Collantes, M. (María)
Peñuelas, I. (Iván)
Diaz-Gonzalez, J.A. (Juan Antonio)
Calvo, A. (Alfonso)
|Issue Date: ||11-May-2010|
|Publisher: ||BIOMED CENTRAL|
|Publisher version: ||http://dx.doi.org/10.1186/1471-2407-10-188|
|Citation: ||Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M, et al. Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer 2010 May 11;10:188.|
Background: There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs)
leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have
been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine
kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast
cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC).
Methods: We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2.
Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed in
vitro. In vivo experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without
radiotherapy) were also carried out.
Results: Lapatinib dramatically reduced cell proliferation (P < 0.0001), DNA synthesis (P < 0.006), and colony formation
capacity (P < 0.0001) in A549 cells in vitro. Furthermore, lapatinib induced G1 cell cycle arrest (P < 0.0001) and apoptotic
cell death (P < 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages,
respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active
caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also
demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc
and PCNA levels. In vivo experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly
less active tumors (as assessed by PET analysis) (P < 0.04) and smaller in size than controls. In addition, tumors from
lapatinib-treated mice showed a dramatic reduction in angiogenesis (P < 0.0001).
Conclusion: Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.|
|Permanent link: ||http://hdl.handle.net/10171/13173|
|Appears in Collections:||DA - CIMA - Oncología - Nuevas dianas terapéuticas - Artículos de revista|
DA - Ciencias - HAP - Artículos de revista
DA - CIMA - Servicios de apoyo - Micropet - Artículos de revista
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