orlistat and Breast-Neoplasms
orlistat has been researched along with Breast-Neoplasms* in 5 studies
Other Studies
5 other study(ies) available for orlistat and Breast-Neoplasms
Article | Year |
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Potential of Orlistat to induce apoptotic and antiangiogenic effects as well as inhibition of fatty acid synthesis in breast cancer cells.
Breast cancer as most often women's cancer is the second cause of mortality worldwide. Research interest increased in testing non-standard drugs to suppress breast cancer progression and become significant supplements in anticancer therapy. The anti-obesity drug Orlistat showed significant ability for modulation of cancer cell metabolism via antiproliferative, proapoptotic, antiangiogenic, antimetastatic, and hypolipidemic effects. The anticancer potential of Orlistat was evaluated by cytotoxicity (MTT assay), type of cell death (AO/EB double staining), determination of redox status parameters (superoxide, hydrogen peroxide, lipid peroxidation, reduced glutathione), and total lipid levels with colorimetric methods, as well on angiogenesis-related (VEGF, MMP-9, CXCR4/CXCL12) and fatty acid synthesis-related (ACLY, ACC, FASN) parameters on gene and protein levels (immunocytochemistry and qPCR). Based on obtained results Orlistat induces significant cytotoxic, proapoptotic, and anti-angiogenic effects in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells, without significant cytotoxic effects on normal MRC-5 cells. It decreased total lipid levels and changed redox status parameters and cancer cell metabolism via suppression of genes and proteins involved and fatty acid synthesis. Based on showed, Orlistat may be an important supplement in antiangiogenic therapy against breast cancer with no side effects on normal cells, making it a good candidate for future clinical trials. Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Fatty Acids; Female; Humans; Lactones; Lipids; Orlistat | 2023 |
Development of a Self-Assembled Nanoparticle Formulation of Orlistat, Nano-ORL, with Increased Cytotoxicity against Human Tumor Cell Lines.
Fatty acid synthase (FASN), the enzyme that catalyzes de novo synthesis of fatty acids, is expressed in many cancer types. Its potential as a therapeutic target is well recognized, but inhibitors of FASN have not yet been approved for cancer therapy. Orlistat (ORL), an FDA-approved lipase inhibitor, is also an effective inhibitor of FASN. However, ORL is extremely hydrophobic and has low systemic uptake after oral administration. Thus, new strategies are required to formulate ORL for cancer treatment as a FASN inhibitor. Here, we report the development of a nanoparticle (NP) formulation of ORL using amphiphilic bioconjugates that are derived from hyaluronic acid (HA), termed Nano-ORL. The NPs were loaded with up to 20 wt % weight of ORL at greater than 95% efficiency. The direct inhibition of the human recombinant thioesterase domain of FASN by ORL extracted from Nano-ORL was similar to that of stock ORL. Nano-ORL demonstrated a similar ability to inhibit cellular FASN activity when compared to free ORL, as demonstrated by analysis of (14)C-acetate incorporation into lipids. Nano-ORL treatment also disrupted mitochondrial function similarly to ORL by reducing adenosine triphosphate turnover in MDA-MB-231 and LNCaP cells. Nano-ORL demonstrated increased potency compared to ORL toward prostate and breast cancer cells. Nano-ORL decreased viability of human prostate and breast cancer cell lines to 55 and 57%, respectively, while free ORL decreased viability to 71 and 79% in the same cell lines. Moreover, Nano-ORL retained cytotoxic activity after a 24 h preincubation in aqueous conditions. Preincubation of ORL dramatically reduced the efficacy of ORL as indicated by high cell viability (>85%) in both breast and prostate cell lines. These data demonstrate that NP formulation of ORL using HA-derived polymers retains similar levels of FASN, lipid synthesis, and ATP turnover inhibition while significantly improving the cytotoxic activity against cancer cell lines. Topics: Apoptosis; Breast Neoplasms; Cell Proliferation; Drug Compounding; Enzyme Inhibitors; Fatty Acid Synthases; Fatty Acid Synthesis Inhibitors; Female; Humans; Lactones; Male; Mitochondria; Nanoparticles; Orlistat; Prostatic Neoplasms; Tumor Cells, Cultured | 2016 |
FoxA and LIPG endothelial lipase control the uptake of extracellular lipids for breast cancer growth.
The mechanisms that allow breast cancer (BCa) cells to metabolically sustain rapid growth are poorly understood. Here we report that BCa cells are dependent on a mechanism to supply precursors for intracellular lipid production derived from extracellular sources and that the endothelial lipase (LIPG) fulfils this function. LIPG expression allows the import of lipid precursors, thereby contributing to BCa proliferation. LIPG stands out as an essential component of the lipid metabolic adaptations that BCa cells, and not normal tissue, must undergo to support high proliferation rates. LIPG is ubiquitously and highly expressed under the control of FoxA1 or FoxA2 in all BCa subtypes. The downregulation of either LIPG or FoxA in transformed cells results in decreased proliferation and impaired synthesis of intracellular lipids. Topics: 4-Butyrolactone; Animals; Biological Transport; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Doxycycline; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 3-alpha; Hepatocyte Nuclear Factor 3-beta; Humans; Lactones; Lipase; Lipid Metabolism; MCF-7 Cells; Mice; Mice, Nude; Neoplasm Invasiveness; Orlistat; RNA, Small Interfering; Signal Transduction; Xenograft Model Antitumor Assays | 2016 |
Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene.
Orlistat (Xenicaltrade mark), a US Food and Drug Administration (FDA)-approved drug for bodyweight loss, has recently been demonstrated to exhibit antitumor properties towards prostate cancer cells by virtue of its ability to block the lipogenic activity of fatty acid synthase (FAS). FAS (oncogenic antigen-519) is up-regulated in about 50% of breast cancers, is an indicator of poor prognosis, and has recently been functionally associated with the Her2/neu (erbB-2) oncogene.. We assessed the antitumoral effects of orlistat against the human breast cancer cell line SK-Br3, an in vitro paradigm of FAS and Her2/neu overexpression in breast cancer.. Cell cycle analyses revealed that micromolar concentrations of orlistat induced, in a time- and dose-dependent manner, significant changes in the distribution of cell populations including a complete loss of G2-M phase, S-phase accumulation and a concomitant increase in the emerging sub-G1 (apoptotic) cells. Poly (ADP-ribose) polymerase (PARP) cleavage, an early event required for cells committed to apoptosis, was more predominant in orlistat-treated G1 phase cells. When we characterized signaling molecules participating in the cellular events following orlistat-induced inhibition of FAS activity and preceded inhibition of breast cancer cell proliferation, a dramatic down-regulation of Her2/neu-coded p185(Her2/neu) oncoprotein was found in orlistat-treated SK-Br3 cells (>90% reduction). Interestingly, a significant accumulation of the DNA-binding protein PEA3, a member of the Ets transcription factor family that specifically targets a PEA3-binding motif present on the Her2/neu gene promoter and down-regulates its activity, was observed in orlistat-treated SK-Br3 cells. When a Luciferase reporter gene driven by the Her2/neu promoter was transiently transfected in SK-Br3 cells, orlistat exposure was found to dramatically repress the promoter activity of Her2/neu gene, whereas a Her2/neu promoter bearing a mutated binding DNA sequence was not subject to negative regulation by orlistat, thus demonstrating that the intact PEA3 binding site on the Her2/neu promoter is required for the orlistat-induced transcriptional repression of Her2/neu overexpression. RNA interference (RNAi)-mediated silencing of FAS gene expression similarly repressed Her2/neu gene expression in a PEA3-dependent manner, thus ruling out a role for non-FAS orlistat-mediated effects. When the combination of orlistat and the anti-Her2/neu antibody trastuzumab (Herceptintrade mark) in either concurrent (orlistat + trastuzumab) or sequential (orlistat --> trastuzumab; trastuzumab --> orlistat) schedules was tested for synergism, addition or antagonism using the combination index (CI) method of Chou-Talalay, co-exposure of orlistat and trastuzumab demonstrated strong synergistic effects (CI10-90 = 0.110-0.847), whereas sequential exposure to orlistat followed by trastuzumab (CI10-90 = 0.380-1.210) and trastuzumab followed by orlistat (CI10-90 = 0.605-1.278) mainly showed additive or antagonistic interactions. Indeed, orlistat-induced FAS inhibition synergistically promoted apoptotic cell death wh. These findings reveal that the development of more potent and/or bioavailable orlistat's variants targeting the lipogenic activity of FAS may open a novel therapeutic avenue for treating Her2/neu-overexpressing breast carcinomas. Topics: Anti-Obesity Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Down-Regulation; Drug Synergism; Drug Therapy, Combination; fas Receptor; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Lactones; Lipase; Luciferases; Orlistat; Poly(ADP-ribose) Polymerases; Promoter Regions, Genetic; Receptor, ErbB-2; Receptors, Tumor Necrosis Factor; RNA, Small Interfering; Transcription Factors; Transcription, Genetic; Trastuzumab; Tumor Cells, Cultured | 2005 |
Outdated and misleading review of orlistat.
Topics: Anti-Obesity Agents; Bias; Breast Neoplasms; Dietary Fats; Female; Humans; Lactones; Obesity; Orlistat; Treatment Outcome | 1999 |