Impact of alendronate and VEGF-antisense combined treatment on highly VEGF-expressing A431 cells

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 TGFα secretion. It was only at 48h 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 VEGFantisense oligonucleotide. The combination of such an antisense with small concentrations of alendronate (~2 µM), which is of the order of clinically used concentrations, was shown to have an antiangiogenic effect as soon as 12h.

Formation of 1-Hydroxymethylene-1,1-bisphosphinates through the Addition of a Silylated Phosphonite on Various Trivalent Derivatives

“…HMBPs have high affinity for hydroxyapatite, which is the main mineral found in bones, and they can chelate several metal ions, such as Mg­(+II), Ca­(+II), and Fe­(+II). HMBPs which are easily taken up by the bone tissue are usually used as inhibitors of bone resorption and more precisely in osteoporosis, solid tumor bone metastases, and myeloma bone disease . These compounds also exhibit interesting antitumor effects on soft tissue primary tumor models (breast, prostate, etc.…”

“…These compounds also exhibit interesting antitumor effects on soft tissue primary tumor models (breast, prostate, etc. ). , However, their uses are limited by their unfavorable pharmacokinetics and biodistribution. In fact, bisphosphonates hardly pass the biological membranes due to their negative charges at physiological pH.…”

From Industrial Method to the Use of Silylated P(III) Reagents for the Synthesis of Relevant Phosphonylated Molecules

“…These compounds are less toxic and present few side effects. BPs also exhibit direct and indirect antitumor effects in vitro against a broad variety of tumor cell lines, including melanoma, mesothelioma, prostate, breast, lung, and myeloma cancer cell …”

Effect of shRNA-mediated knockdown of vascular endothelial growth factor on the proliferation of choroid-retinal endothelial cells under hypoxic conditions

“…Inhibitors for VEGF include anti-VEGF antibodies (such as bevacizumab, a recombinant human VEGF antibody) (7), soluble VEGF receptors (such as pegaptanib, a VEGF-165 RNA antagonist) (8), VEGF receptor antagonists, antisense VEGF (9) and VEGF-associated signal pathway inhibitors. Although these drugs may be useful for the inhibition of retinal neovascularization, and a number of these drugs have been used in a clinical context, one issue with their application is the requirement for frequent administration in order to maintain a suppressive effect against VEGF.…”