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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Impact of alendronate and VEGF-antisense combined treatment on highly VEGF-expressing A431 cells
Medge Mongerard-Coulanges1, Evelyne Migianu-Griffoni, Marc Lecouvey
1Laboratoire de Biophysique Moleculaire, Cellulaire et Tissulaire, CNRS, UMR 7033, France.
Abstract:
Bisphosphonates, and more specially nitrogen-containing bisphosphonates, which are in current use for the treatment of bone diseases, demonstrate proapoptotic, antiproliferative, antiangiogenic and anti-invasive properties on tumor cells. The amino-bisphosphonate alendronate is considered as a potential anticancer drug. In the case of A431 cells, which express high levels of VEGF, it had a two-step effect. At 24h, the antitumor properties of alendronate were counterbalanced by a survival process, which consisted of an enhancement of VEGF expression (mRNA and protein secretion) and TGF alpha secretion. It was only at 48 h that alendronate displayed the expected antiproliferative and antiangiogenic properties. The first step, in which the PI3K pathway was engaged, could be prevented by the use of a VEGF-antisense oligonucleotide. The combination of such an antisense with small concentrations of alendronate (approximately 2 microM), which is of the order of clinically used concentrations, was shown to have an antiangiogenic effect as soon as 12h.
Insights
Alendronate shows anti-cancer effects by inhibiting tumor cell growth and angiogenesis. Combining alendronate with VEGF-antisense oligonucleotides enhances its anti-cancer properties, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Bisphosphonates, particularly nitrogen-containing ones, exhibit anti-cancer properties like apoptosis induction and anti-proliferation.
- Alendronate, an amino-bisphosphonate, is explored for its potential as an anti-cancer agent.
- A431 cells, characterized by high VEGF expression, were used to study alendronate's effects.
Purpose of the Study:
- To investigate the time-dependent anti-cancer effects of alendronate on tumor cells.
- To elucidate the role of VEGF and TGF-alpha in mediating alendronate's early effects.
- To evaluate the potential of combining alendronate with VEGF-targeted therapy for enhanced anti-cancer activity.
Main Methods:
- Treatment of A431 cells with alendronate at different time points (24h and 48h).
- Assessment of VEGF and TGF-alpha expression (mRNA and protein).
- Utilized VEGF-antisense oligonucleotides to investigate pathway involvement and combined effects with alendronate.
Main Results:
- Alendronate exhibited a biphasic effect: initial pro-survival response (increased VEGF and TGF-alpha) at 24h, followed by anti-proliferative and anti-angiogenic effects at 48h.
- The early survival response involved the PI3K pathway and was mediated by enhanced VEGF expression.
- Combination therapy with alendronate (2 microM) and VEGF-antisense oligonucleotide demonstrated significant anti-angiogenic effects as early as 12h.
Conclusions:
- Alendronate's anti-cancer efficacy is time-dependent, with an initial counteracting survival mechanism.
- Targeting VEGF signaling, particularly in combination with alendronate, can overcome the initial resistance and enhance anti-cancer outcomes.
- This combination strategy holds promise for early and effective anti-angiogenic therapy in cancer treatment.
