ArticleBritish journal of cancer2008
Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells.
Article in British journal of cancer, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 45 citations in OpenAlex.
- Phosphodiesterase Inhibition to Sensitize Non-Small-Cell Lung Cancer to Pemetrexed: A Double-Edged Strategy.Cancers · 2024Article
- Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2021Review
- Molecular mechanism underlying the pharmacological interactions of the protein kinase C-β inhibitor enzastaurin and erlotinib in non-small cell lung cancer cells.American journal of cancer research · 2017Article
- Protein kinase Cα mediates erlotinib resistance in lung cancer cells.Molecular pharmacology · 2015Article
- Review
- Pemetrexed induces S-phase arrest and apoptosis via a deregulated activation of Akt signaling pathway.PloS one · 2014Article
- Thymidylate synthase expression determines pemetrexed targets and resistance development in tumour cells.PloS one · 2013Article
- Enzastaurin has anti-tumour effects in lung cancers with overexpressed JAK pathway molecules.British journal of cancer · 2012Article
- Protein kinase C-beta inhibition induces apoptosis and inhibits cell cycle progression in acquired immunodeficiency syndrome-related non-hodgkin lymphoma cells.Journal of investigative medicine : the official publication of the American Federation for Clinical Research · 2012Article
- The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma.PloS one · 2012Article
- Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin.British journal of cancer · 2011Article
- Sp1 inhibition-mediated upregulation of VEGF 165 b induced by rh-endostatin enhances antiangiogenic and anticancer effect of rh-endostatin in A549.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2011Article
- Enzastaurin inhibits invasion and metastasis in lung cancer by diverse molecules.British journal of cancer · 2010Article
- Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation.Translational oncology · 2009Article
- MET/PKCbeta expression correlate with metastasis and inhibition is synergistic in lung cancer.Journal of carcinogenesis · 2009Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKC beta inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription-PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3 beta and Akt phosphorylation, which was additionally reduced by drug combination (-58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (>50% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients.
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