Nanoparticles loaded with ferrocenyl tamoxifen derivatives for breast cancer treatment.

International audienceFor the first time, two organometallic triphenylethylene compounds (Fc-diOH and DFO), with strong antiproliferative activity in breast cancer cells, but insoluble in biological fluids, were incorporated in two types of stealth nanoparticles (NP): PEG/PLA nanospheres (NS) and nanocapsules (NC). Their physicochemical parameters were measured (size, zeta potential, encapsulation and loading efficiency), and their biological activity was assessed. In vitro drug release after high dilution of loaded NPs was measured by estradiol binding competition in MELN cells. The influence of the encapsulated drugs on the cell cycle and apoptosis was studied by flow cytometry analyses. Notwithstanding potential drug adsorption at the NP surface, Fc-diOH and DFO were incorporated efficiently in NC and NS, which slowly released both compounds. They arrested the cell cycle in the S-phase and induced apoptosis, whose activity is increased by loaded NS. A decrease in their antiproliferative activity by the antioxidant alpha-tocopherol indicated that reactive oxygen species (ROS) may be involved. Therefore, nanosystems, containing for the first time a high load of anticancer organometallic triphenylethylenes, have been developed. Their small size and delayed drug release, combined with their enhanced apoptotic potential, are compatible with an increased persistence in the blood and a promising antitumour activity

Anticancer Drugs in Liposomal Nanodevices: A Target Delivery for a Targeted Therapy

International audienceFor many years, nanocarriers have been investigated to modify pharmacokinetics and biodistribution of various active molecules. In the cancer domain, one of the biggest challenges still remains the improvement of the therapeutic index, often too low, for the majority of antitumor drugs. The application of nanotechnologies for the treatment and the diagnosis of cancers are nowadays currently developed, or under development, and liposomes play an important role in the history of nanodevices. Because of their high degree of biocompatibility, lipid nanosystems have been used to improve pharmacological profiles of various anticancer drugs otherwise discarded because of their low water solubility, poor bioavailability or either fragile and subjected to rapid biotransformations. This review aims at introducing an overview of the last 40 years of liposome researches until the last liposomal formulations commercially available or undergoing clinical trials. Liposome properties will be described, with a particular emphasis over the last generation of carriers appreciated for their active targeting characteristics. Researchers foresee a remarkable impact of nanotechnologies in the field of medicine; this review will try to summarize the main concepts over liposome domain, which can count on encouraging results as target therapy associated with targeted delivery

Estrogen receptor signaling as a target for novel breast cancer therapeutics.: new targets in estradiol receptor-positive breast cancers

International audienceIn breast cancer (BC) epithelial cells, the mitogenic action of estradiol is transduced through binding to two receptors, ERα and ERβ, which act as transcription factors. Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC. In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors. Estrogen effects are mediated not only through nuclear ERs but also through cytoplasmic/membrane ERs and G-protein-coupled ERs. These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival. The partners of nuclear ER include SRC1-3, HDACs and ERβ itself as well as newly identified proteins, such as E6-AP, LKB1, PELP1, PAX-2 and FOXA1. The partners of extra-nuclear ERα include PI3K and the tyrosine kinase Src. These various factors are all potential targets for therapeutic intervention. In addition, BC proliferation is enhanced by insulin and EGF, which stimulate signaling through the MAPK and PI3K/AKT pathways by activation of the IGF-1R and EGFR axes, respectively. These pathways are tightly interconnected with ER-activated signaling, and membrane ERα forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response. Inhibiting these pathways with specific inhibitors or activating some of the pathways by gene manipulation may be therapeutically valuable for arresting BC cell cycle progression and for inducing apoptosis to antagonize hormone-resistance. Here, we review some newly identified putatively targetable ER partners and highlight the need to develop tumor-targeting drug carrier systems affecting both the tumor cells and the tumor environment

Various Phosphorylation Pathways, Depending on Agonist and Antagonist Binding to Endogenous Estrogen Receptor α (ERα), Differentially Affect ERα Extractability, Proteasome-Mediated Stability, and Transcriptional Activity in Human Breast Cancer Cells

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Transcriptional repression of the tyrosinase-related protein 2 gene by transforming growth factor-β and the Kruppel-like transcription factor GLI2

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Chromatin structure of hormono-dependent promoters

International audienceTransient transfections of mutated MMTV LTRs, driving the luciferase reporter gene, have shown the presence of at least one cis-acting element cooperating with the GREs. Studies of the chromatin structure of two glucocorticoid-regulated promoters, the mouse mammary tumor virus (MMTV) long terminal repeat (LTR), a retroviral promoter, and the rat tyrosine aminotransferase (TAT) promoter, demonstrate that both DNAs are organized into precisely positioned nucleosomes. Hormonal activation of transcription is accompanied by structural changes of one (MMTV LTR) or two (TAT promoter) nucleosomes associated with the hormone-response elements (HREs). These changes can be visualized by the appearance of DNasel hypersensitive sites. Association of the hormone-receptor complex with the nucleus is necessary to induce the DNasel hypersensitive site and to maintain transcription, but is not necessary to maintain DNasel hypersensitivity. Anti-hormones, even when able to promote a strong binding of the receptor to the nucleus, are unable to induce the chromatin structural change. Using cell lines containing approx. 200 copies of a MMTV LTR/Hv-ras chimeric construct, we have demonstrated a strong, hormono-independent nuclear matrix interaction of sequences located just upstream and downstream of the ras coding sequences

Liposomal trichostatin A: therapeutic potential in hormone-dependent and -independent breast cancer xenograft models

International audienceTrichostatin A (TSA) is one of the most potent histone deacetylase inhibitors (HDACi) in vitro but it lacks biological activity in vivo when injected intravenously owing to its fast metabolism

The Selective Estrogen Receptor Modulator 4-Hydroxy Tamoxifen Induces G1 Arrest and Apoptosis of Multiple Myeloma Cell Lines

International audienceMultiple myeloma (MM) is an incurable hematological malignancy for which new therapeutic strategies should be envisaged. The selective estrogen receptor modulator (SERM), 4-hydroxy tamoxifen (4-OHTam), in the range of 1 to 10 micro M, was able to impair the cell proliferation of MM cell lines. This was achieved by blocking cells at the G1 phase of the cell cycle and by inducing apoptosis. This cellular response was observed in five out of six tested cell lines, all five expressing both alpha and beta estrogen receptor forms. No modifications of Bcl-2, Bcl-X, and Bax levels were observed, as well as no changes in Pi3K/Akt and JAK/STAT pathways that are often constitutively active in these cells. The signalization of 4-OHTam-induced cell death needs further investigation