A new dimethyl ester bisphosphonate inhibits angiogenesis and growth of human epidermoid carcinoma xenograft in nude mice

Abstract

Bisphosphonates are extensively used in the treatment of patients with metastasis-induced osteolysis. The major drawback in the efficacy of all bisphosphonates lies in their high hydrophilic nature, which results in poor membrane permeability and low availability for soft tissues. A reasonable approach to overcome these problems consists in masking one or more ionizable groups of bisphosphonates, notably by esterification of the hydroxyl functions. We have previously shown that the novel non-nitrogen-containing bisphosphonate BP7033 inhibited angiogenesis and growth of primary tumors in nude mice. The present study focuses on the dimethyl-esterified analog of this compound (Me-BP7033). In-vitro, Me-BP7033 inhibited proliferation of human carcinoma A431 cells as well as their invasive activity based on a transwell invasion assay. in-vivo, administration of Me-BP7033 (0.3 mg/kg) twice a week for 5 weeks inhibited the tumor growth of A431 cells xenografted in nude mice by 65%. Immunostaining of endothelial cells (ECs) in tumor sections revealed that Me-BP7033 inhibited the intratumor ECs density by 60%. The in-vivo anti-angiogenic properties of Me-BP7033 were also demonstrated in an in-vivo angiogenesis assay showing that Me-BP7033 reduced the vascular endothelial growth factor-stimulated infiltration of ECs in a Matrigel plug by 70%. In summary, we demonstrated for the first time that a diesterified bisphosphonate exhibited in vivo both anti-tumoral and anti-angiogenic activities with no apparent sign of toxic effects. These new diesterified compounds, which could display enhanced bioavailability and pharmacokinetics, thus represent interesting candidates for therapeutic applications such as cancer treatment.

New Experimental Therapies Targetting Breast Cancer Cell

“…BP7033Br ALK reduces MDA-MB-231 and D3H2LN cell viabilities about 90% with a concentration 4-fold inferior to that of BP7033Br. These data are in agreement with previous results on epidermoid A431 cell proliferation that show a beneficial effect of esterification of the phosphonic groups (Guenin et al, 2005;Ledoux et al, 2006). Our hypothesis is that such esterified compounds rendered BPs more hydrophobic increasing their cell uptake and could therefore act like prodrugs releasing active BP into the cells.…”

“…Previously, new strategy to overcome BP hydrophilicity is masking the phosphonic acid with organic protecting groups and introducing hydrophobic functions in the side chain (Migianu et al, 2005). An esterified BP with methyl group displays antitumor growth and antiangiogenic activities on A431 tumors, being more effective in vivo than in vitro (Ledoux et al, 2006). In order to further increase the lipophilicity of BPs (and their entering into the cells), we have synthesized new aromatic 1-hydroxymethylene-1,1-bisphosphonic acids containing phenyl or halogen phenyl ring in their side chains.…”

Structural Requirements for Bisphosphonate Binding on Hydroxyapatite: NMR Study of Bisphosphonate Partial Esters

“…A BP P,P′-dimethylester showed both antitumoral and antiangiogenic activity in nude mice with human epidermoid carcinoma xenografts. 23 Interestingly, a BP tetraisopropylester, apomine, was found to inhibit the growth of several different tumor cell lines when used in micromolar concentrations. 24 It reached an open-label, nonrandomized phase II trial in 2001 for the treatment of metastatic melanoma.…”

“…28,29 The stability of the aforementioned BP dimethylester (E) having both antitumor and antiangiogenic activity was investigated in vitro to evaluate its resistance toward enzymatic hydrolysis, but no significant amount of the corresponding BP acid was detected, though no data was shown to support this finding. 23 This indicates the methylester to be stable against enzymatic hydrolysis and that it could induce anticancer mechanisms as such. It was also stated that when the enzymatic hydrolysis tests were conducted with the BP diphenylester (F), at least 50% of the diphenylester was hydrolyzed into its corresponding monophenylester or tetra acid form.…”

Effect of the cumulative dose of zoledronic acid on the pathogenesis of osteonecrosis of the jaws

“…In addition, BPs are reported to exert direct antiproliferative and proapoptotic effects on cancer cells, thereby reducing bone metastases (9,10). Furthermore, BPs alter angiogenesis (11) and signal transduction between osteoclasts and osteoblasts (12). Depending on the presence or absence of a nitrogen atom, nitrogen-containing and non-nitrogen-containing BPs differ in the mechanism of action exerted on osteoclasts (13,14).…”