New Symmetrically Esterified m-Bromobenzyl Non-Aminobisphosphonates Inhibited Breast Cancer Growth and Metastases

1 - ArticleBACKGROUND: Although there was growing evidence in the potential use of Bisphosphonates (BPs) in cancer therapy, their strong osseous affinities that contrast their poor soft tissue uptake limited their use. Here, we developed a new strategy to overcome BPs hydrophilicity by masking the phosphonic acid through organic protecting groups and introducing hydrophobic functions in the side chain. METHODOLOGY/PRINCIPAL FINDINGS: We synthesized non-nitrogen BPs (non N-BPs) containing bromobenzyl group (BP7033Br) in their side chain that were symmetrically esterified with hydrophobic 4-methoxphenyl (BP7033BrALK) and assessed their effects on breast cancer estrogen-responsive cells (T47D, MCF-7) as well as on non responsive ones (SKBR3, MDA-MB-231 and its highly metastatic derived D3H2LN subclone). BP7033Br ALK was more efficient in inhibiting tumor cell proliferation, migration and survival when compared to BP7033Br. Although both compounds inhibited tumor growth without side effects, only BP7033Br ALK abrogated tumor angiogenesis and D3H2LN cells-induced metastases formation. CONCLUSION/SIGNIFICANCE: Taken together these data suggest the potential therapeutic use of this new class of esterified Bisphosphonates (BPs) in the treatment of tumor progression and metastasis without toxic adverse effects

The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study: baseline participant profile.

The aim of the study was to examine baseline neurocognitive impairment (NCI) prevalence and factors associated with NCI among patients enrolled in the Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study. The NAMACO study is an ongoing, prospective, longitudinal, multicentre and multilingual (German, French and Italian) study within the Swiss HIV Cohort Study. Between 1 May 2013 and 30 November 2016, 981 patients ≥ 45 years old were enrolled in the study. All underwent standardized neuropsychological (NP) assessment by neuropsychologists. NCI was diagnosed using Frascati criteria and classified as HIV-associated or as related to other factors. Dichotomized analysis (NCI versus no NCI) and continuous analyses (based on NP test z-score means) were performed. Most patients (942; 96.2%) had viral loads < 50 HIV-1 RNA copies/mL. NCI was identified in 390 patients (39.8%): 263 patients (26.8%) had HIV-associated NCI [249 patients (25.4%) had asymptomatic neurocognitive impairment (ANI)] and 127 patients (13%) had NCI attributable to other factors, mainly psychiatric disorders. There was good correlation between dichotomized and continuous analyses, with NCI associated with older age, non-Caucasian ethnicity, shorter duration of education, unemployment and longer antiretroviral therapy duration. In this large sample of aging people living with HIV with well-controlled infection in Switzerland, baseline HIV-associated NCI prevalence, as diagnosed after formal NP assessment, was 26.8%, with most cases being ANI. The NAMACO study data will enable longitudinal analyses within this population to examine factors affecting NCI development and course

Invading Basement Membrane Matrix Is Sufficient for MDA-MB-231 Breast Cancer Cells to Develop a Stable In Vivo Metastatic Phenotype

1 - ArticleIntroduction: The poor efficacy of various anti-cancer treatments against metastatic cells has focused attention on the role of tumor microenvironment in cancer progression. To understand the contribution of the extracellular matrix (ECM) environment to this phenomenon, we isolated ECM surrogate invading cell populations from MDA-MB-231 breast cancer cells and studied their genotype and malignant phenotype. Methods: We isolated invasive subpopulations (INV) from non invasive populations (REF) using a 2D-Matrigel assay, a surrogate of basal membrane passage. INV and REF populations were investigated by microarray assay and for their capacities to adhere, invade and transmigrate in vitro, and to form metastases in nude mice. Results: REF and INV subpopulations were stable in culture and present different transcriptome profiles. INV cells were characterized by reduced expression of cell adhesion and cell-cell junction genes (44% of down regulated genes) and by a gain in expression of anti-apoptotic and pro-angiogenic gene sets. In line with this observation, in vitro INV cells showed reduced adhesion and increased motility through endothelial monolayers and fibronectin. When injected into the circulation, INV cells induced metastases formation, and reduced injected mice survival by up to 80% as compared to REF cells. In nude mice, INV xenografts grew rapidly inducing vessel formation and displaying resistance to apoptosis. Conclusion: Our findings reveal that the in vitro ECM microenvironment per se was sufficient to select for tumor cells with a stable metastatic phenotype in vivo characterized by loss of adhesion molecules expression and induction of proangiogenic and survival factors

Angiotensin II Facilitates Breast Cancer Cell Migration and Metastasis

Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN) were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre-treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors

Activités antiproliférative et antiangiogénique des dérivés du dextrane en association avec le phénylacétate de sodium et interactions avec le VEGF

PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Effets anti-métastatiques de nouveaux m-bromobenzyl bisphosphonates non azotés et caractérisation de nouvelles lignées invasives issues d un adénocarcinome métastatique de sein (MDA-MB-231)

La progression métastatique est la cause majeure de mortalité liée au cancer. L approfondissement des connaissances sur la formation des métastases permet d améliorer les traitements existants et d identifier de nouvelles cibles thérapeutiques. La première partie de ce travail nous a permis de démontrer l efficacité d une nouvelle génération de bisphosphonates (BPs) non azotés avec un groupement bromo-benzyl au niveau de leur chaine latérale et avec ou sans alkylation des groupements phosphonates (BP7033Br et BP7033Br ALK). Ces deux BPs sont capables, in vitro, d inhiber la prolifération, la motilité et l invasion des cellules de cancer du sein MDA-MB-231. De plus, ils sont capables d inhiber, in vivo, la croissance et l angiogenèse tumorale chez la souris athymique. Seul le BP7033Br ALK est capable d inhiber la formation des métastases osseuses et extra-osseuses dans un modèle de progression métastatique utilisant un système d imagerie par bioluminescence IVIS (xenogen). Ce résultat montre que l estérification des groupements phosphonates améliore les propriétés des BPs notamment au niveau des tissues extra-osseux et permet d envisager de nouvelles applications thérapeutiques. La deuxième partie a permis d établir et de caractériser, in vitro et in vivo, deux nouvelles lignées cellulaires INV (invasive) et REF (référence) ayant des capacités invasives différentes. Les cellules INV sont 4 fois plus invasives que les cellules REF. Dans cette étude nous avons montré, in vitro, que les cellules INV prolifèrent moins rapidement, qu elles sont plus résistantes à l apoptose et qu elles expriment plus du facteur angiogéniques et ses récepteurs (VEGF, VEGFR2 et NRP1). In vivo, les cellules INV sont capables de développer des tumeurs sous-cutanées, plus volumineuses et plus angiogéniques par rapport aux cellules REF. En injectant ces deux lignées en intracardiaque, nous avons montré que les cellules INV forment plus de sites métastatiques par rapport aux cellules REF et diminue la survie des souris. L ensemble de ce travail montre d une part l intérêt de l estérification des groupements phosphonates pour cibler des métastases autres qu osseuses, et d autre part le rôle important du phénotype invasif d une lignée de cancer de sein métastatique, dans la progression tumorale.The metastatic progression is the main cause of death in cancer. Increasing our knowledge of the molecular and cellular mechanism of the formation of metastasis possibly allow to identify new treatments. In the first part of this work, we developed two new bisphosphonates (m-Bromobenzyl non-aminobisphosphonates; BP7033Br and symmetrically esterified with hydrophobic 4-methoxphenyl; BP7033Br ALK ) in order to develp new strategy to overcome BPs hydrophilicity by masking the phosphonic acid through organic protecting groups and introducing hydrophobic functions in the side chain.We have demonstrated that BP7033Br and BP7033Br ALK inhibited, in vitro, the proliferation, motility and invasion of MDA-MB-231 breast cancer cells. Although both compounds inhibited tumor growth without side effects, only the BP7033Br ALK abrogated D3H2LN cell-induced metastases formation. In the second part of this work, we have isolated two invasive subpopulations from MDA-MB-231 cells using Matrigel coated Boyden chambers. We showed that very invasive cells designed INV cells, were 4-fold and 3-fold more invasive and motile than non invasive ones (REF cells), respectively. INV cells were less adhesive than REF cells to endothelial cells or to the major ECM component, fibronectin. Although INV subpopulation cells grew 2-fold slower than REF cells in vitro, tumors from INV cells xenografted in nude mice presented higher volume and more angiogenesis. This angiogenesis phenotypic difference was associated with a more important expression in VEGF, NRP-1 and VEGFR2 receptors. In addition, we showed that INV cells were more resistant to doxorubicin treatment as well as to growth factors starvation. INV cells when injected into blood circulation of nude mice induced more metastasis sites as compared to REF ones and dramatically diminished of about 80% the mice survival. Transcriptomic analysis of INV and REF cells showed modulation of genes expression involved in adhesion and resistance to apoptosis. In conclusion, invasive phenotype was sufficient to induce metastasis formation correlated with poor endothelial and ECM adhesion, survival and angiogenesis abilities.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Aponecrotic, antiangiogenic and antiproliferative effects of a novel dextran derivative on breast cancer growth in vitro and in vivo

International audience1 Since the sodium phenylacetate (NaPa) was reported to enhance the inhibitory effect of carboxymethyl benzylamide dextran (CMDB) on the breast cancer growth, we performed the esterification of CMDB with NaPa to obtain a new drug carrying the characteristics of these two components. A new molecule, phenylacetate carboxymethyl benzylamide dextran, was named NaPaC. We investigated in vitro and in vivo the effects of NaPaC on MCF‐7ras cell growth as well as its apoptotic and antiangiogenic effects in comparison to NaPa and CMDB. In addition, we assessed in vitro the antiproliferative effects of these drugs on other breast cancer cells, including MDA‐MB‐231, MDA‐MB‐435 and MCF‐7. In vitro , NaPaC inhibited MCF‐7ras cell proliferation by 40% at concentration lower than that of CMDB and NaPa (12 μ M vs 73 μ M and 10 m M ). IC 50 s were 6 and 28 μ M for NaPaC and CMDB, respectively. The similar results were obtained for three other breast cancer cell lines. NaPaC reduced the DNA replication and induced cell recruitment in G 0 /G 1 phase more efficiently than its components. Moreover, it induced a cell death at concentration 1000‐fold lower than NaPa. In vivo , CMDB (150 mg kg −1 ) and NaPa (40 mg kg −1 ) inhibited the MCF‐7ras tumour growth by 37 and 57%, respectively, whereas NaPaC (15 mg kg −1 ) decreased tumour growth by 66% without toxicity. NaPa or CMDB reduced the microvessel number in tumour by 50% after 7 weeks of treatment. NaPaC had the same effect after only 2 weeks. After 7 weeks, it generated a large necrosis area without detectable microvessels. In vitro , NaPaC inhibited human endothelial cell proliferation more efficiently than CMDB or NaPa. NaPaC interacts with vascular endothelial growth factor as observed by affinity electrophoresis. NaPaC acts like NaPa and CMDB but in more potent manner than components used separately. Its antiproliferative, aponecrotic and anti‐angiogenic actions make it a good candidate for a new anti‐cancer drug. British Journal of Pharmacology (2002) 135 , 1859–1871; doi: 10.1038/sj.bjp.070464

A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis

International audienc

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

International audienc

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

International audienc