deoxycholic-acid and Breast-Neoplasms

Paclitaxel leads to peripheral neuropathy (paclitaxel-induced peripheral neuropathy [PIPN]) in approximately 50% of cancer patients. At present, there are no effective treatment strategies for PIPN, the mechanisms of which also remain unclear. In this study, we performed microbiome and metabolome analysis of feces and serum from breast cancer patients with different PIPN grades due to paclitaxel treatment. Our analysis reveals that levels of deoxycholic acid (DCA) are highly increased because of ingrowth of Clostridium species, which is associated with severe neuropathy. DCA, in turn, elevates serum level of C-C motif ligand 5 (CCL5) and induces CCL5 receptor 5 (CCR5) overexpression in dorsal root ganglion (DRG) through the bile acid receptor Takeda G-protein-coupled receptor 5 (TGR5), contributing to neuronal hyperexcitability. Consistent with this, administration of CCR5 antagonist maraviroc suppresses the development of neuropathic nociception. These results implicate gut microbiota/bile acids/CCR5 signaling in the induction of PIPN, thus suggesting a target for PIPN treatment.

Topics: Breast Neoplasms; Deoxycholic Acid; Female; Humans; Maraviroc; Neuralgia; Paclitaxel; Receptors, CCR5

A growing body of evidence indicates that the dysbiosis of both mammary and intestinal microbiota is associated with the initiation and progression of breast tumors. However, the microbial characteristics of patients with breast tumors vary widely across studies, and replicable biomarkers for early-stage breast tumor diagnosis remain elusive.. We demonstrate a machine learning-based method for the analysis of breast tissue and gut microbial differences among patients with benign breast disease, patients with breast cancer (BC), and healthy individuals using 16S rRNA sequence data retrieved from eight studies. QIIME 2.0 and R software (version 3.6.1) were used for consistent processing. A naive Bayes classifier was trained on the RDP v16 reference database to assign taxonomy using the Vsearch software.. The results of this study will improve our understanding of the microbial profile of breast tumors. Changes in the microbial population may be present in both the tissues and the gut of patients with BC, and specific markers could aid in the early diagnosis of BC. The findings from

Topics: Bayes Theorem; Biomarkers, Tumor; Breast Neoplasms; Clostridium; Deoxycholic Acid; Feces; Female; Gastrointestinal Microbiome; Humans; RNA, Ribosomal, 16S

Bile acids (BAs) are bioactive molecules that have potential therapeutic interest and their derived salts are used in several pharmaceutical systems. BAs have been associated with tumorigenesis of several tissues including the mammary tissue. Therefore, it is crucial to characterize their effects on cancer cells. The objective of this work was to analyse the molecular and cellular effects of the bile salts sodium cholate and sodium deoxycholate on epithelial breast cancer cell lines. Bile salts (BSs) effects over breast cancer cells viability and proliferation were assessed by MTS and BrdU assays, respectively. Activation of cell signaling mediators was determined by immunobloting. Microscopy was used to analyze cell migration, and cellular and nuclear morphology. Interference of membrane fluidity was studied by generalized polarization and fluorescence anisotropy. BSs preparations were characterized by transmission electron microscopy and dynamic light scattering. Sodium cholate and sodium deoxycholate had dual effects on cell viability, increasing it at the lower concentrations assessed and decreasing it at the highest ones. The increase of cell viability was associated with the promotion of AKT phosphorylation and cyclin D1 expression. High concentrations of bile salts induced apoptosis as well as sustained activation of p38 and AKT. In addition, they affected cell membrane fluidity but not significant effects on cell migration were observed. In conclusion, bile salts have concentration-dependent effects on breast cancer cells, promoting cell proliferation at physiological levels and being cytotoxic at supraphysiological ones. Their effects were associated with the activation of kinases involved in cell signalling.

Topics: Bile Acids and Salts; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deoxycholic Acid; Humans; Sodium Cholate

Clinical studies have found that the incidence of cancer metastasis through the lymphatic vessels are 3-5 times higher than that through the blood vessels. These findings suggest the potency of anti-lymphangiogenic therapy in reducing the incidence of cancer metastasis. Previously, we reported LHbisD4, which is the conjugate of low molecular weight heparin (LMWH) and four bis-deoxycholates as a potent anti-angiogenic drug with less toxicity and orally active property. Here, we show that LHbisD4 could also suppress the formation of new lymphatic vessels and attenuate the incidence of metastasis by blocking VEGF-C signaling pathway. LHbisD4 significantly enhanced binding affinity with VEGF-C when compared with LMWH, which enables LHbisD4 to suppress the proliferation, migration and formation of tubular structures of human dermal lymphatic endothelial cells(HDLECs) in in vitro condition even in the presence of excessive amounts of VEGF-C. Similarly, we found that the density of lymphatic vessels in the primary tumor tissue in breast cancer bearing mice was significantly diminished when LHbisD4 was administered compared with the control group. Also, the incidence of axillary lymph nodes and distant organ metastasis was significantly reduced in the LHbisD4 administered group, which demonstrates that LHbisD4 could successfully lower the incidence of metastasis through blocking VEGF-C induced lymphangiogenesis. Based on these results, we propose LHbisD4 as a potent anti-cancer drug that can reduce the incidence of metastasis by suppressing lymphangiogenesis through blocking VEGF-C signaling pathway.

Topics: Angiogenesis Inhibitors; Animals; Breast Neoplasms; Cell Movement; Cell Proliferation; Deoxycholic Acid; Endothelial Cells; Female; Heparin, Low-Molecular-Weight; Humans; Lymph Nodes; Lymphangiogenesis; Lymphatic Metastasis; Lymphatic Vessels; Mice; Mice, Inbred BALB C; Mice, SCID; Neovascularization, Pathologic; Vascular Endothelial Growth Factor C

Targeting multiple stages in metastatic breast cancer is one of the effective ways to inhibit metastatic progression. To target human metastatic breast cancer as well as improving patient compliance, we developed an orally active low molecular weight heparin (LMWH)-taurocholate conjugated with tetrameric deoxycholic acid, namely LHTD4, which followed by physical complexation with a synthetic bile acid enhancer, DCK. In breast cancer, both transforming growth factor-β1 (TGF-β1) and CXCL12 exhibit enhanced metastatic activity during the initiation and progression stages of breast cancer, thus we direct the focus on investigating the antimetastatic effect of LHTD4/DCK complex by targeting TGF-β1 and CXCL12. Computer simulation study and SPR analysis were performed for the binding confirmation of LHTD4 with TGF-β1 and CXCL12. We carried out in vitro phosphorylation assays of the consecutive receptors of TGF-β1 and CXCL12 (TGF-β1R1 and CXCR4, respectively). Effects of LHTD4 on in vitro cell migration (induced by TGF-β1) and chemotaxis (mediated by CXCL12) were investigated. The in vivo anti-metastatic effect of LHTD4 was evaluated in an accelerated metastasis model and an orthotopic MDA-MB-231 breast cancer model. The obtained KD values of TGF-β1 and CXCL12 with LHTD4 were 0.85 and 0.019 μM respectively. The simulation study showed that binding affinities of LHTD4 fragment with either TGF-β1 or CXCL12 through additional electrostatic interaction was more stable than that of LMWH fragment. In vitro phosphorylation assays of TGF-β1R1 and CXCR4 showed that the effective inhibition of receptor phosphorylation was observed with the treatment of LHTD4. The expressions of epithelial to mesenchymal transition (EMT) marker proteins such as vimentin and Snail were prevented by LTHD4 treatment in in vitro studies with TGF-β1 treated MDA-MB-231 cells. Moreover, we observed that LHTD4 negatively regulated the functions of TGF-β1 and CXCL12 on migration and invasion of breast cancer cell. In several advanced orthotopic and experimental breast cancer metastasis murine models, the treatment with LHTD4 (5 mg/kg daily, p.o.) significantly inhibited metastasis compared to the control. Overall, LHTD4 exhibited anti-metastatic effects by inhibiting TGF-β1 and CXCL12, and the clinically relevant dose of orally active LHTD4 was found to be effective in preclinical studies without any apparent toxicity.

Topics: Animals; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Chemokine CXCL12; Deoxycholic Acid; Epithelial-Mesenchymal Transition; Female; Heparin, Low-Molecular-Weight; Humans; Mice, SCID; Molecular Targeted Therapy; Neoplasm Metastasis; Phosphorylation; Taurocholic Acid; Transforming Growth Factor beta1

Hydrophobically-modified polymers based on chondroitin sulfate with different degree of substitution (DS) of deoxycholic acid (DOCA) were developed for docetaxel delivery. Chondroitin sulfate-deoxycholic acid (CSAD) bioconjugates were synthesized via the linker of adipic dihydrazide by amide bond. They were characterized with spherical shape, mean diameter of around 165.2nm and negative zeta potential (-14.87 to -20.53mV). An increase of DOCA DS reduced size of nanoparticles, while increasing drug loading efficiency. Drug release in vitro showed a triphasic sustained pattern and higher accumulative drug release percentage was observed with increased DS of DOCA on polymer. Self-assemblies with higher DS also had enhanced internalization of nanoparticles and stronger cytotoxicity at the cellular level. The self-assemble nanoparticles demonstrate to be excellent targeting drug delivery systems and the desired therapeutics can be achieved via the alteration of DS.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Chondroitin Sulfates; Deoxycholic Acid; Docetaxel; Drug Carriers; Drug Delivery Systems; Drug Liberation; Female; Humans; Hydrophobic and Hydrophilic Interactions; Nanoparticles; Polymers; Taxoids; Tumor Cells, Cultured

Although curcumin (CUR) can inhibit proliferation and induce apoptosis of tumors, the poor water solubility restricted its clinical application. The aim of this study was to improve the aqueous solubility of CUR and make more favorable changes to bioactivity by preparing curcumin-loaded phospholipid-sodium deoxycholate-mixed micelles (CUR-PC-SDC-MMs). CUR-PC-SDC-MMs were prepared by the thin-film dispersion method. Based on the results of single factor exploration, the preparation technology was optimized using the central composite design-response surface methodology with drug loading and entrapment efficiency (EE%) as indicators. The images of transmission electron microscopy showed that the optimized CUR-PC-SDC-MMs were spherical and well dispersed. The average size of the mixed micelles was 66.5 nm, the zeta potential was about -26.96 mV and critical micelle concentration was 0.0087 g/l. CUR was encapsulated in PC-SDC-MMs with loading capacity of 13.12%, EE% of 87.58%, and the solubility of CUR in water was 3.14 mg/ml. The release results in vitro showed that the mixed micelles presented sustained release behavior compared to the propylene glycol solution of CUR. The IC50 values of CUR-loaded micelles and free drug in human breast carcinoma cell lines were 4.10 μg/ml and 6.93 µg/ml, respectively. It could be concluded from the above results that the CUR-PC-SDC-MMs system might serve as a promising nanocarrier to improve the solubility and bioactivity of CUR.

Topics: Antineoplastic Agents; Breast Neoplasms; Chemistry, Pharmaceutical; Curcumin; Delayed-Action Preparations; Deoxycholic Acid; Drug Carriers; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; Micelles; Microscopy, Electron, Transmission; Particle Size; Phospholipids; Solubility

Lipid nanocapsules (LNC) are usually developed as nanocarriers for lipophilic drug delivery. The surface characteristics of these colloidal particles are determinant for a controlled and directed delivery to target tissues with specific markers. We report the development of immuno-nanocapsules, in which some antibody molecules with different immuno-specificity are conjugated to the nanocapsule surface, offering the standardization of a simple method to obtain vectorized nanosystems with specific recognition properties. Nanocapsules were prepared by a solvent-displacement technique, producing an oily core coated by a functional shell of different biocompatible molecules and surface carboxylic groups. Three different antibodies (one a specific HER2 oncoprotein antibody) were conjugated with these nanoparticles by the carbodiimide method, which allows the covalent immobilization of protein molecules through carboxylic surface groups. The immuno-nanocapsules were completely characterized physico-chemically via electrokinetic and colloidal stability experiments, confirming the correct immobilization of these antibody molecules on the colloidal nanoparticles. Also, additional immunological analyses verified that these IgG-LNC complexes showed the expected specific immuno-response. Finally, different healthy and tumoral breast-cell lines were cultured in vitro with Nile-Red-loaded and docetaxel-loaded HER2 immuno-nanocapsules. The results indicate that our immuno-nanocapsules can increase their uptake in HER2 overexpressing tumoral cell lines.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Colloids; Deoxycholic Acid; Docetaxel; Drug Screening Assays, Antitumor; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; Nanocapsules; Olive Oil; Particle Size; Plant Oils; Poloxamer; Receptor, ErbB-2; Taxoids; Trastuzumab

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Chemistry, Pharmaceutical; Chitosan; Delayed-Action Preparations; Deoxycholic Acid; Drug Carriers; Drug Compounding; Epoxy Compounds; Female; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Kinetics; Microscopy, Confocal; Nanoparticles; Nanotechnology; Paclitaxel; Particle Size; Propanols; Quaternary Ammonium Compounds; Solubility; Surface-Active Agents; Technology, Pharmaceutical

Bone is the most common site to which breast cancer cells metastasize. We found that osteoblast-like MG63 cells and human bone tissue contain the bile acid salt sodium deoxycholate (DC). MG63 cells take up and accumulate DC from the medium, suggesting that the bone-derived DC originates from serum. DC released from MG63 cells or bone tissue promotes cell survival and induces the migration of metastatic human breast cancer MDA-MB-231 cells. The bile acid receptor farnesoid X receptor (FXR) antagonist Z-guggulsterone prevents the migration of these cells and induces apoptosis. DC increases the gene expression of FXR and induces its translocation to the nucleus of MDA-MB-231 cells. Nuclear translocation of FXR is concurrent with the increase of urokinase-type plasminogen activator (uPA) and the formation of F-actin, two factors critical for the migration of breast cancer cells. Our results suggest a novel mechanism by which DC-induced increase of uPA and binding to the uPA receptor of the same breast cancer cell self-propel its migration and metastasis to the bone.

Topics: Actins; Bone and Bones; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Survival; Culture Media, Conditioned; Deoxycholic Acid; DNA-Binding Proteins; Female; Humans; Lipids; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Urokinase-Type Plasminogen Activator

High concentrations of plasma deoxycholic acid (DCA) are found in human breast cyst fluid and it has been hypothesised that this may be related to risk of breast cancer. The aim of this pilot study was to ascertain whether plasma bile acid concentrations were greater in women with breast cancer.. A case-control study comparing postmenopausal women with breast cancer with healthy controls was conducted.. Twenty Caucasian postmenopausal breast cancer patients were recruited at the time of diagnosis together with 20 healthy controls matched for age and body mass index. Exclusion criteria included any treatment for breast cancer, use of hormone replacement therapy in the last 12 months, diabetes mellitus, a history of liver or gall bladder disease or abnormal liver function.. Fasting plasma bile acid concentrations were determined by gas-liquid chromatography/mass spectrometry.. The mean plasma DCA concentration was 52% higher (P=0.012) in patients with breast cancer compared with controls.. These results support the hypothesis that DCA may be involved in the aetiology of breast cancer.

Topics: Aged; Breast Neoplasms; Case-Control Studies; Deoxycholic Acid; Female; Gas Chromatography-Mass Spectrometry; Humans; Middle Aged; Postmenopause

Topics: Aged; Bile Acids and Salts; Body Mass Index; Breast Neoplasms; Case-Control Studies; Cholic Acid; Deoxycholic Acid; Female; Humans; Middle Aged; Postmenopause; Risk Factors