stearates and Breast-Neoplasms

Objective: Paclitaxel (PTX) is a chemotherapeutic agent used for treating breast cancer. The study aimed to prepare\ PTX loaded dextran stearate (Dex-SA) and evaluate its efficacy against human breast cancer cell line MCF-7. Methods:\ Dex-SA/PTX micelles were prepared by dialysis method. The micelles size, zeta potential and particle size distribution\ were measured by dynamic laser light scattering method. Amount of loaded PTX on the polymer measured by HPLC.\ Release profiles of the drug from the micelles were obtained in buffer (phosphate pH=7.4). Then the cytotoxicity of blank\ micelles, Dex-SA/PTX micelles and free PTX were evaluated in the MCF-7 cells by MTT method. Result: Loading\ efficiency of PTX on the Dex-SA was measured about 84.24±9.07%. The smallest particles size was about 193.9±7.1\ nm but the other formulation with larger particle size had better zeta potential (-33.5±6.74 mV). The drug release\ from the micelles was slowly and reached steady state after about 12 hours. The cytotoxicity experiment showed that\ Dex-SA/PTX micelles have more cytotoxicity compared to free PTX against MCF7 cell lines. Conclusions: Dex-SA\ polymeric micelle is a suitable carrier for hydrophobic cytotoxic drugs such as PTX.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Proliferation; Dextrans; Drug Liberation; Female; Humans; Micelles; Paclitaxel; Polymers; Stearates; Tumor Cells, Cultured

Chemical synthesis and characterization of a lipophilic ester conjugate, propofol stearate and evaluation of its anticancer efficacy on human breast cancer cell lines MDA-MB-361, MCF-7 and MDA-MB-231.. The chemical structure of the synthesized conjugate was characterized by spectroscopic studies. Its anticancer potential was evaluated on the basis of growth inhibition, cancer cell adhesion and migration and apoptosis induction.. Propofol stearate exhibited significant (p<0.05) growth inhibition of breast cancer cells in a concentration-dependent manner. MDA-MB-231 cells showed highest susceptibility towards the inhibitory effect of the conjugate. Moreover, treatment of MDA-MB-231 cancer cells with 25 μM propofol stearate potentially suppressed their adhesion (~34%) and migration (~41%), and induced apoptosis (~25%).. Exogenously-applied stearic acid as an ester derivative, inhibits the growth of human breast cancer cells and shows a beneficial role in the treatment of breast cancer, in vitro.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Design; Esters; Female; Humans; Propofol; Stearates; Stearic Acids

Multidrug resistance (MDR) and drug toxicity are two major factors responsible for the failure of cancer chemotherapy. Herein the efficacy and safety of combination therapy using doxorubicin (Dox, D)-mitomycin C (MMC, M) co-loaded stealth polymer-lipid hybrid nanoparticles (DMsPLNs) were evaluated in sensitive and MDR human mammary tumor xenografts. DMsPLN demonstrated enhanced efficacy compared to liposomal Dox (PLD) with up to a 3-fold increase in animal life span, a 10-20% tumor cure rate, undetectable normal tissue toxicity and decreased tumor angiogenesis. These results suggest DMsPLN have potential as an effective treatment of breast cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Combinations; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Lipids; Mice; Mice, Nude; Mitomycin; Nanoparticles; Polyethylene Glycols; Random Allocation; Stearates; Xenograft Model Antitumor Assays

Previous studies have shown that stearate (C18:0), a dietary long-chain saturated fatty acid, inhibits breast cancer cell neoplastic progression; however, little is known about the mechanism modulating these processes. We demonstrate that stearate, at physiological concentrations, inhibits cell cycle progression in human breast cancer cells at both the G(1) and G(2) phases. Stearate also increases cell cycle inhibitor p21(CIP1/WAF1) and p27(KIP1) levels and concomitantly decreases cyclin-dependent kinase 2 (Cdk2) phosphorylation. Our data also show that stearate induces Ras- guanosine triphosphate formation and causes increased phosphorylation of extracellular signal-regulated kinase (pERK). The MEK1 inhibitor, PD98059, reversed stearate-induced p21(CIP1/WAF1) upregulation, but only partially restored stearate-induced dephosphorylation of Cdk2. The Ras/mitogen-activated protein kinase/ERK pathway has been linked to cell cycle regulation but generally in a positive way. Interestingly, we found that stearate inhibits both Rho activation and expression in vitro. In addition, constitutively active RhoC reversed stearate-induced upregulation of p27(KIP1), providing further evidence of Rho involvement. To test the effect of stearate in vivo, we used the N-Nitroso-N-methylurea rat breast cancer carcinogen model. We found that dietary stearate reduces the incidence of carcinogen-induced mammary cancer and reduces tumor burden. Importantly, mammary tumor cells from rats on a stearate diet had reduced expression of RhoA and B as well as total Rho compared with a low-fat diet. Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo.

Topics: Animals; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Diet, Fat-Restricted; Extracellular Signal-Regulated MAP Kinases; Female; Flow Cytometry; Humans; Phosphorylation; ras Proteins; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; rho GTP-Binding Proteins; RNA, Messenger; Signal Transduction; Stearates; Tumor Burden; Tumor Cells, Cultured

Stearate is an 18-carbon saturated fatty acid found in many foods in the western diet, including beef and chocolate. Stearate has been shown to have anti-cancer properties during early stages of neoplastic progression. However, previous studies have not investigated the effect of dietary stearate on breast cancer metastasis. In this study, we present evidence that exogenously supplied dietary stearate dramatically reduces the size of tumors that formed from injected human breast cancer cells within the mammary fat pads of athymic nude mice by approximately 50% and partially inhibits breast cancer cell metastasis burden in the lungs in this mouse model system. This metastatic inhibition appears to be independent of primary tumor size, as stearate fed animals that had primary tumors comparable in size to littermates fed either a safflower oil enriched diet or a low fat diet had reduced lung metastasis. Also stearate fed mice sub-groups had different primary tumor sizes but no difference in metastasis. This anti-metastasis effect may be due, at least in part, to the ability of stearate to induce apoptosis in these human breast cancer cells. Overall, this study suggests the possibility of dietary manipulation with selected long-chain saturated fatty acids such as stearate as a potential adjuvant therapeutic strategy for breast cancer patients wishing to maximize the suppression of metastatic disease.

Topics: Animal Feed; Animals; Breast Neoplasms; Cell Line, Tumor; Dietary Fats; Disease Progression; Female; Humans; Linoleic Acid; Lung; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Stearates

DRM (detergent-resistant membranes), which are resistant to solublization by non-ionic detergents, have been demonstrated to be involved in many key cell functions such as signal transduction, endocytosis and cholesterol trafficking. Covalent modification of proteins by fatty acylation has been proposed to be an important protein-targeting mechanism for DRM association. However, little is known concerning the effects of LCSFA (long-chain saturated fatty acids) on protein composition of DRM in human cancer cells. In the present study, we found that, in Hs578T human breast cancer cells, the major protein increased in DRM in response to the LCSFA stearate (C18:0) was annexin II. Our results demonstrated that annexin II accumulated in DRM specifically in response to physiological concentrations of stearate and palmitate (C16:0), but not long-chain unsaturated fatty acids, in a time- and concentration-dependent manner. This process was reversible and dependent on cholesterol and intracellular calcium. Although calcium was necessary for this translocation, it was not sufficient to induce the annexin II translocation to DRM. We also demonstrate that stearate induced the acylation of caveolin but not that of annexin II. Association of annexin II with caveolin, although not necessarily direct, specifically occurs in DRM in response to stearate. Finally, bromostearate, a stearate analogue that effectively blocks protein acylation, does not induce annexin II translocation to DRM. We conclude that exogenously added LCSFA strongly induces the translocation of annexin II to DRM in Hs578T human breast cancer cells at least partially by association with acylated caveolin.

Topics: Acylation; Annexin A2; Breast Neoplasms; Cell Line, Tumor; Detergents; Fatty Acids; Humans; Membrane Microdomains; Palmitates; Protein Transport; Stearates

Long chain saturated fatty acids are known to inhibit breast cancer cell proliferation; however, the mechanism of this inhibition is not known. Treatment of Hs578T breast cancer cells with long chain saturated fatty acids (0.15 mmol/L for 6 hours) before epidermal growth factor (EGF) treatment inhibited EGF-induced cell proliferation in a chain-length-dependent manner. Stearate (C:18) completely inhibited the EGF-induced cell proliferation, whereas palmitate (C:16) inhibited by 67 +/- 8% and myristate (C:14) had no effect. In contrast, stearate had little effect on insulin-like growth factor-1-stimulated cell proliferation. The inhibitory effect of stearate on cell proliferation was dose and time dependent and independent of EGF receptor (EGFR) tyrosine phosphorylation. Pretreatment of cells with pertussis toxin (0.1 microgram/ml for 24 hours) inhibited the EGF-induced cell growth by 50 +/- 8%, also independent of EGFR tyrosine phosphorylation. A pertussis-toxin-sensitive, 41-kd G-protein was specifically co-immunoprecipitated with the EGFR. Pretreatment of cells with 0.15 mmol/L stearate from 0 to 6 hours inhibits, in parallel, both the EGF-induced cell proliferation and pertussis-toxin-catalyzed ADP ribosylation of the G-protein associated with the EGFR. These studies suggest that long chain saturated fatty acids inhibit EGF-induced breast cancer cell growth via a mechanism involving an EGFR-G-protein signaling pathway.

Topics: Adenosine Diphosphate Ribose; Breast Neoplasms; Cell Division; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; GTP-Binding Proteins; Humans; Pertussis Toxin; Recombinant Proteins; Stearates; Thymidine; Tumor Cells, Cultured; Virulence Factors, Bordetella