Synthesis and Biological Activity of 3-(Heteroaryl)quinolin-2(1)-ones Bis-Heterocycles as Potential Inhibitors of the Protein Folding Machinery Hsp90.

In the context of our SAR study concerning 6BrCaQ analogues as C-terminal Hsp90 inhibitors, we designed and synthesized a novel series of 3-(heteroaryl)quinolin-2(1), of types , , and , as a novel class of analogues. A Pd-catalyzed Liebeskind-Srogl cross-coupling was developed as a convenient approach for easy access to complex purine architectures. This series of analogues showed a promising biological effect against MDA-MB231 and PC-3 cancer cell lines.

Synthesis and antiproliferative activity of 6BrCaQ-TPP conjugates for targeting the mitochondrial heat shock protein TRAP1.

A series of 6BrCaQ-C-TPP conjugates 3a-f and 5 was designed and synthesized as a novel class of TRAP1 inhibitors. Compound 3a displayed an excellent anti-proliferative activity with mean GI values at a nanomolar level in a diverse set of human cancer cells (GI = 0.008-0.

Assessment of various formulation approaches for the application of beta-lapachone in prostate cancer therapy.

Beta-lapachone (β-Lap) is an anticancer drug activated by the NAD(P)H:quinone oxidoreductase (NQO1), an enzyme over-expressed in a large variety of tumors. B-Lap is poorly soluble in water and in most biocompatible solvents. Micellar systems, liposomes and cyclodextrins (CDs) have been proposed for its solubilization.

Cancer drug resistance: rationale for drug delivery systems and targeted inhibition of HSP90 family proteins.

Nanocarriers have been developed in order to protect drugs or to improve drugs efficiency by reaching the damaged tissue and avoiding systemic and local toxicity. By using HSP90 inhibitors, some cancer drug resistances have been overcome and the loading into nanocarriers of such drugs has shown an increase of their activities. This review will present some advantages of HSP90 inhibitors to treat resistant tumors; especially those targeting the mitochondrial protein TRAP1.

Hybrid Lipid Polymer Nanoparticles for Combined Chemo- and Photodynamic Therapy.

Retinoblastoma is a malignant tumor of the retina in infants. Conventional therapies are associated to severe side effects and some of them induce secondary tumors. Photodynamic therapy (PDT) thus appears as a promising alternative as it is nonmutagenic and generates minimal side effects.

Interaction of dequalinium chloride with phosphatidylcholine bilayers: A biophysical study with consequences on the development of lipid-based mitochondrial nanomedicines.

Dequalinium (DQ) has been proposed as a mitochondrial targeting ligand for nanomedicines, including liposomes, given the implication of these organelles in many diseases. This original study focuses on the interactions of DQ with phosphatidylcholine bilayers during the formation of liposomes. Firstly, PEGylated liposomes suitable for drug delivery were studied and were found to be more stable when made in water than in phosphate-buffered saline, emphasizing the role of electrostatic interactions between positive charges on DQ and the polar head groups of the lipids.

Antitumor activity of nanoliposomes encapsulating the novobiocin analog 6BrCaQ in a triple-negative breast cancer model in mice.

In this study, we investigated the anticancer efficacy of pegylated liposomes containing 6BrCaQ, an hsp90 inhibitor derived from novobiocin. 6BrCaQ has been previously identified as the most potent compound in a series of quinoleic novobiocin analogs but is poorly water-soluble. We investigated, for the first time, the anti-proliferative effects of this drug in vivo in an orthotopic breast cancer model (MDA-MB-231 luc) using pegylated liposomes to allow its administration.

Surface-Modified Biodegradable Nanoparticles' Impact on Cytotoxicity and Inflammation Response on a Co-Culture of Lung Epithelial Cells and Human-Like Macrophages.

The toxicity of polymeric biodegradable nanoparticles was evaluated on a co-culture made from direct contact of human lung alveolar epithelial cells (A459) and macrophages (differentiated THP-1 monocytes). The co-culture was characterized by its phenotype and by confocal laser scanning microscopy. Cytokine secretion induced by lipopolysaccharide was synergistically increased in the co-culture confirming cell-cell interactions.

The Use of Nanocarriers in Acute Myeloid Leukaemia Therapy: Challenges and Current Status.

Chemotherapy for AML is hampered by severe side-effects and failure to eliminate all the blasts that eventually leads to relapse. The use of nanosized particulate drug carriers such as liposomes and polymeric nanoparticles has the potential to improve AML therapy by delivering more of the drug to the disease site, thereby reducing toxicity. For example, encapsulation in liposomes reduces the cardiotoxicity of anthracyclines, giving an improved therapeutic index.

Immunonutrition stimulates immune functions and antioxidant defense capacities of leukocytes in radiochemotherapy-treated head & neck and esophageal cancer patients: A double-blind randomized clinical trial.

Background: Immunonutrition has been reported to improve the immune status of perioperative cancer patients, thereby reducing complications and length of hospital stay.

Aim: This study aimed to assess whether immunonutrition enriched in arginine, EPA & DHA and nucleotides could impact the immune cells responses in head & neck and esophageal cancer patients treated by radiochemotherapy (RCT).

Methods: A double-blind clinical trial was carried out in 28 patients randomized into two groups, receiving either an immunomodulating enteral nutrition formula (IEN, n = 13, Impact(®), Nestlé) or an isoenergetic isonitrogenous standard enteral nutrition formula (SEN, n = 15) throughout RCT (5-7 weeks).

Synthesis and antiproliferative activity of novobiocin analogues as potential hsp90 inhibitors.

A series of substituted coumarins1-10 was designed and synthesized as a novel class of 4TCNA analogues. Compound 2a showed excellent antiproliferative activity with mean GI50 values at a micromolar level in a diverse set of human cancer cells (GI50 = 2-30 μM) and induced a high apoptosis level in MCF-7 breast cancer cell line. The molecular signature of hsp90 inhibition was assessed by depletion of the Erα hsp90 client protein.

Epigallocatechin gallate (EGCG) prevents H2O2-induced oxidative stress in primary rat retinal pigment epithelial cells.

Purpose: To determine whether the green tea polyphenol epigallocatechin gallate (EGCG) could prevent H(2)O(2)-induced oxidative stress in primary rat retinal pigment epithelial cells.

Methods: Primary cultures of retinal pigment epithelium (RPE) cells were established from Long-Evans newborn rats. RPE cells were pretreated with various concentrations of EGCG for 24 h before being exposed to hydrogen peroxide (H(2)O(2)) for 2 h to induce oxidative stress.

Orange juice and its major polyphenol hesperidin consumption do not induce immunomodulation in healthy well-nourished humans.

Background & Aims: Polyphenols exert a variety of biological properties, including antioxidant, immunomodulatory and antigenotoxic effects. In a randomized crossover study in healthy men, we investigated the effects of orange juice and its major polyphenolic compound hesperidin on a panel of immune cell functions, including cytokine secretion by leukocytes, lytic activity of NK cells, and the Reactive Oxygen Species (ROS) burst by polymorphonuclear neutrophil cells (PMN).

Methods: The protocol design was divided into three 4-week treatment periods separated by 3-week wash-out intervals, for total study duration of 18 weeks.

Altered functions of natural killer cells in response to L-Arginine availability.

L-Arginine (L-Arg) availability is crucial in the regulation of immune response. Indeed, L-Arg deficiency induces T-cell dysfunction and could modulate the properties of natural killer (NK) cells involved in the early host defense against infections and tumors. We explored the impact of L-Arg depletion on NK cell functions using two models - an NK-92 cell line and isolated human blood NK cells.

E-selectin as a target for drug delivery and molecular imaging.

E-selectin, also known as CD62E, is a cell adhesion molecule expressed on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation and in the adhesion of metastatic cancer cells to the endothelium. E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes.

Lemon verbena infusion consumption attenuates oxidative stress in dextran sulfate sodium-induced colitis in the rat.

Background: Inflammatory bowel diseases (IBD) consist of an uncontrolled intestinal inflammation leading to mucosal disruption. This inflammation is accompanied by an excessive production of reactive oxygen species (ROS). Polyphenols are micronutrients with antioxidative and anti-inflammatory properties, and may play an interesting role in the prevention of intestinal inflammation.

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

Background: Trichostatin 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.

Materials And Methods: TSA was incorporated into Stealth® liposomes (TSA-lipo) at a high loading and its anticancer activity was evaluated in several types of breast cancer cells and xenografts.

Results: In estrogen receptor α (ERα)-positive MCF-7 and T47-D cells, TSA induced a long-term degradation of cyclin A and a proteasome-dependent loss of ERα and cyclin D1, allowed derepression of p21WAF1/CIP1, HDAC1 and RhoB GTPase, concomitantly with blockade in G2/M of the cell cycle and apoptosis induction.