TY - JOUR
T1 - Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth
T2 - A new paradigm for understanding the therapeutic effect of combined treatment
AU - Ortholan, Cécile
AU - Durivault, Jérôme
AU - Hannoun-Levi, Jean Michel
AU - Guyot, Mélanie
AU - Bourcier, Christine
AU - Ambrosetti, Damien
AU - Safe, Stephen
AU - Pags, Gilles
N1 - Funding Information:
This work was supported by the ‘Centre National pour la Recherche Scientifique’, the University of Nice Sophia Antipolis, the ‘Ligue Nationale Contre le Cancer’ Equipe Labellisée, the Association for International Cancer Research (AICR), the National Institute of Cancer (INCA), the Association for Cancer Research (ARC, contract 4932) and the Cancéropole PACA. We thank Roche-France for financial support. C.O., J.D., A.V., C.B. and G.P. performed the experiments, S.S. provided plasmids, J.M.H.L. has initiated the work, C.O. and G.P. wrote the manuscript. We thank Dr. M.C. Brahimi-Horn for editorial correction of the manuscript.
Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/11
Y1 - 2010/11
N2 - Bevacizumab (Bvz), a Vascular Endothelial Growth Factor (VEGF)-targeted humanised monoclonal antibody, provides clinical benefit in combination with docetaxel (DXL), a microtubule-stabilising agent, in the treatment of metastatic breast and prostate cancers. Since VEGF and their receptors are expressed by tumour cells, we hypothesised that Bvz, in addition to its impact on neo-vascularisation, could have an impact on tumour cells and enhance the DXL activity. Hence, we studied the effect of DXL and Bvz on metastatic breast (MDA MB-231) and prostate (PC3) cancer cells lines. Bvz alone did not decrease cell proliferation but in combination with DXL, Bvz enhanced the anti-proliferative activity of DXL. Other anti-angiogenic factors Sunitinib, Sorafenib and Gefitinib enhanced the anti-proliferative effect of DXL. qPCR experiments showed that DXL significantly increased the VEGF and VEGF receptor 2 (VEGF-R2) mRNA levels. Activation of VEGF and VEGF-R2 promoters demonstrated that enhanced mRNA levels are partly due to transcriptional activation. ELISA assays showed that DXL induced accumulation of cytoplasmic VEGF but decreased extracellular levels by 39% (MDA) and 48% (PC3). Cell surface localisation of VEGF-R2 was increased by DXL alone, but decreased after combined treatment of DXL plus Bvz. Abnormal expression of VEGF-R2 was also shown on breast and prostate tumour samples reinforcing the results obtained on cellular models. In conclusion, DXL and Bvz in combination decreased extracellular VEGF and VEGF-R2 levels at the plasma membrane thereby blocking an important growth/survival loop. Thus, the combined therapeutic impact of Bvz and DXL observed in clinical trials is associated with enhanced anti-proliferative activity and inhibition of the vascular network.
AB - Bevacizumab (Bvz), a Vascular Endothelial Growth Factor (VEGF)-targeted humanised monoclonal antibody, provides clinical benefit in combination with docetaxel (DXL), a microtubule-stabilising agent, in the treatment of metastatic breast and prostate cancers. Since VEGF and their receptors are expressed by tumour cells, we hypothesised that Bvz, in addition to its impact on neo-vascularisation, could have an impact on tumour cells and enhance the DXL activity. Hence, we studied the effect of DXL and Bvz on metastatic breast (MDA MB-231) and prostate (PC3) cancer cells lines. Bvz alone did not decrease cell proliferation but in combination with DXL, Bvz enhanced the anti-proliferative activity of DXL. Other anti-angiogenic factors Sunitinib, Sorafenib and Gefitinib enhanced the anti-proliferative effect of DXL. qPCR experiments showed that DXL significantly increased the VEGF and VEGF receptor 2 (VEGF-R2) mRNA levels. Activation of VEGF and VEGF-R2 promoters demonstrated that enhanced mRNA levels are partly due to transcriptional activation. ELISA assays showed that DXL induced accumulation of cytoplasmic VEGF but decreased extracellular levels by 39% (MDA) and 48% (PC3). Cell surface localisation of VEGF-R2 was increased by DXL alone, but decreased after combined treatment of DXL plus Bvz. Abnormal expression of VEGF-R2 was also shown on breast and prostate tumour samples reinforcing the results obtained on cellular models. In conclusion, DXL and Bvz in combination decreased extracellular VEGF and VEGF-R2 levels at the plasma membrane thereby blocking an important growth/survival loop. Thus, the combined therapeutic impact of Bvz and DXL observed in clinical trials is associated with enhanced anti-proliferative activity and inhibition of the vascular network.
KW - Angiogenesis
KW - Bevacizumab
KW - Breast and prostate tumours
KW - Docetaxel
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UR - http://www.scopus.com/inward/citedby.url?scp=78049318854&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2010.07.021
DO - 10.1016/j.ejca.2010.07.021
M3 - Article
C2 - 20729074
AN - SCOPUS:78049318854
SN - 0959-8049
VL - 46
SP - 3022
EP - 3036
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 16
ER -