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Racane L.,University of Zagreb | Tralic-Kulenovic V.,University of Zagreb | Pavelic S.K.,University of Rijeka | Ratkaj I.,University of Rijeka | And 8 more authors.
Journal of Medicinal Chemistry | Year: 2010

A series of new diamidino-, diisopropylamidino-, and diimidazolinyl- substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes were successfully prepared and evaluated for their antiproliferative activity on tumor cell lines in vitro, DNA binding propensity, and sequence selectivity as well as cellular distribution. A strong antiproliferative effect of the tested compounds was observed on all tested cell lines in a concentration-dependent response pattern. In general, imidazolinyl-substituted derivatives and/or the thiophene core were in correlation with increased antiproliferative activity. Two compounds (2b and 3b) were chosen for biological studies due to their differential antiproliferative properties. The DNA binding properties of this new series of compounds were assessed and evidenced their efficient minor groove binding properties with preferential interaction at AT-rich sites. Both compounds also present nuclear subcellular localization, suggesting that their cellular mode of action implies localization in the DNA compartment and direct inhibition of DNA replication and induction of apoptosis. © 2010 American Chemical Society.

Rebucci M.,French Institute of Health and Medical Research | Rebucci M.,Center Oscar Lambret | Rebucci M.,Institute Pour La Recherche Sur Le Cancer Of Lille Ircl | Peixoto P.,French Institute of Health and Medical Research | And 21 more authors.
International Journal of Oncology | Year: 2011

EGFR is frequently overexpressed in head and neck squamous cell cancer (HNSCC). Cetuximab is a monoclonal antibody designed to interact with EGFR, block its activation, reduce the downstream signaling pathways and induce EGFR internalization. This study aims to investigate the role of the EGFR signaling pathway and EGFR internalization in a cetuximab-resistant cell line and to propose a new therapeutic strategy to optimize treatment of HNSCC. The HNSCC cell line, CAL33 was sensitive to gefitinib but resistant to cetuximab. Cetuximab induces an unexpected EGFR phosphorylation in CAL33 cells similarly to EGF but this EGFR activation does not trigger EGFR internalization/degradation, the process currently implicated in the response to cetuximab. Cetuximab inhibits ERK and AKT phosphorylation in cetuximab-sensitive A431 cells, whereas the level of AKT phosphorylation is unmodified in cetuximab-resistant cells. Interestingly, CAL33 cells harbor a PIK3CA mutation. The treatment of CAL33 cells with PI3K inhibitor and cetuximab restores the inhibition of AKT phosphorylation and induces growth inhibition. Our results indicate that EGFR internalization is impaired by cetuximab treatment in CAL33 cells and that the AKT pathway is a central element in cetuximab resistance. The combination of cetuximab with a PI3K inhibitor could be a good therapeutic option in PIK3CA-mutated HNSCC.

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