Nicole Pommery

Mechanisms leading to COX-2 expression and COX-2 induced tumorigenesis: topical therapeutic strategies targeting COX-2 expression and activity.

The biological role of COX-2, the inducible form of cyclooxygenase, is to convert arachidonic acid into prostaglandins (PGs) and thromboxanes (TXs). Overexpressed in many tumors, COX-2 plays a crucial role in cancer through synthesis of PGs which stimulate PGs receptors with subsequent enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion/motility, and suppression of immune responses. Depending on the tissue specificity and the cell type, several signaling pathways (Kinases, Rho, cGMP and Wnt), and transcription factors such as AP1, NFAT or NF-kappaB, are involved in COX-2 expression. In this review, we will describe mechanisms required by COX-2 metabolites to promote cancer development, and also the signaling pathways leading to COX-2 expression. In order to counteract the negative effects of COX-2 in cancerogenesis, chemicals interfering with COX-2 activity and expression were designed. We will give in the last part of this article, an overview of these potent chemicals interfering with the COX-2 signaling pathways involved in its expression or with its activity.

New advances on prostate carcinogenesis and therapies: involvement of EGF-EGFR transduction system.

The prostate cancers (PCs) are among the major causes of death because therapeutic treatments are not effective against advanced and metastatic forms of this cellular hyperproliferative disorder. In fact, although androgen-deprivation therapies permit to cure localized PC forms, the metastatic PC cells have acquired multiple functional features that confer to them resistance to ionizing radiations and anticarcinogenic drugs currently used in therapy. The present review describes last advances on molecular mechanisms that might be responsible for sustained growth and survival of PC cells. In particular, emphasis is on intracellular signaling cascades which are involved in the mitogenic and antiapoptotic effects of epidermal growth factor EGF-EGFR system. Of therapeutic interest, recent advances and prospects for development of new treatments against incurable forms of metastatic PC forms are also discussed.

Involvement of PI3K/Akt Pathway in Prostate Cancer - Potential Strategies for Developing Targeted Therapies

This review presents some therapeutic interventions actually considered in prostate cancer therapy to compensate constitutive activation of the PI3K/Akt signalling pathway induced, particularly, by mutations of PTEN gene. Special emphasis is placed on applicability of EGF-R tyrosine kinase, COX-2, PDK-1, mTOR and farnesyltransferase inhibitors.

COX-2/5-LOX Dual Acting Anti-Inflammatory Drugs in Cancer Chemotherapy

Emerging reports now indicate alterations of arachidonic acid metabolism with carcinogenesis and many COX and LOX inhibitors (used for the treatment of inflammatory diseases) are being investigated as potential anticancer drugs. Results from clinical trials seem to be encouraging but a better knowledge of the dynamic balance that shifts toward lipoxygenases (and different isoforms of LOXs) and cyclooxygenase-2 are essential to progress in the design of new drugs more specially directed on chemoprevention or chemotherapy of human cancers. So, on the basis of these results, it seemed useful to study the advantages of combination of COX inhibitor with LOX inhibitor and a next step will be the conception of dual inhibitors able to induce the anticarcinogenic and/or to inhibit the procarcinogenic enzymes responsible for polyunsaturated fatty acid metabolism. After a rapid summary of some recent reviews published on the involvement of different COX and LOX isoforms present in human cells, we will discuss on cross-talk reported between the downstream pathways which contribute to the development and progression of human cancers. This will lead us to evoke and to justify alternative strategies to develop agents that modulate multiple targets simultaneously with the aim of enhancing efficacy or improving safety relative to drugs that address only a single enzyme.

Synergistic antiproliferative and apoptotic effects induced by epidermal growth factor receptor and protein kinase a inhibitors in human prostatic cancer cell lines

Our results revealed that the blockade of epidermal growth factor receptor (EGFR) tyrosine kinase and protein kinase A (PKA) signaling pathways by specific inhibitors (PD153035 and Rp‐cAMPs) leads to a synergistic inhibition of EGF‐ and serum‐stimulated growth of human prostatic cancer cells (LNCaP, DU145 and PC3) concomitant with an arrest in the G1 phase of cellular cycle. Of particular interest, the combination of PD153035 and Rp‐cAMPs also caused a more substantial apoptotic/necrotic death of these prostatic cancer cells as compared to drugs alone. Moreover, we observed that the inhibition of acidic sphingomyelinase and caspase cascades results in a marked reduction of DNA fragmentation and apoptotic death induced by PD153035, alone or in combination with Rp‐cAMPs, in EGF stimulated PC3 cells. This suggests that these agents might mediate their cytotoxic effects at least in part via the ceramide generation and activation of caspase signaling pathways. N‐oleoylethanolamine (OE), an inhibitor of acidic ceramidase, consistently potentiated the apoptotic effects of PD153035 in all the prostatic cancer cell lines tested. Additionally, the cellular ceramide content estimated for PC3 cells was increased after treatment with PD153035, alone or in combination, at a lower dose with OE and Rp‐cAMPs.The synergistic apoptotic effect of PD153035 plus Rp‐cAMPs induced in PC3 was also accompanied by a significant rate of mitochondrial membrane depolarization and release of cytochrome c into cytosol as compared to drugs alone. Combined, the results indicated that the simultaneous inhibition of EGFR and PKA signaling cascades might lead to a more massive apoptotic death of metastatic prostatic cancer cells by increasing ceramide accumulation and activating of caspase cascade of a mitochondrial dependent manner.

Assembly/Disassembly of Drug Conjugates Using Imide Ligation

A strategy is described that allows the easy assembly and controlled disassembly of drug conjugates. Imide ligation, that is, the reaction of a peptide thioacid with an azidoformate, is used for conjugate assembly. The imide bond participates also with an endopeptidase-triggered cyclization-based disassembly mechanism.

High-performance liquid chromatography assay of bleomycin in human plasma and rat hepatocytes in culture

SummaryA sensitive and rapid linear-gradient, ionpaired, reversed-phase high-performance liquid chromatography technique using fluorescence detection was developed to quantify bleomycin (BLM) metabolites in the plasma of patients undergoing BLM therapy and in rat hepatocytes that had previously been incubated with 5×10−5m BLM. We could detect about 70 ng/ml using this procedure. BLM metabolites were assayed in the supernatant fractions of precipitated human plasma and in pellets of rat hepatocytes. Metabolite concentrations were below the level of detection in human plasma samples. In hepatocyte pellets, metabolites such as deamido-BLM A2 and deamido-BLM B2 were detected, indicating that isolated rat hepatocytes in culture can metabolize BLM analogues to the corresponding deamido-BLMs. The high-performance liquid chromatography procedure developed during this work can be used to study the metabolism of BLM in cell-culture systems.

Derivatives of Iressa, a Specific Epidermal Growth Factor Receptor Inhibitor, are Powerful Apoptosis Inducers in PC3 Prostatic Cancer Cells

The tyrosine kinase activity of the epidermal growth factor receptor (EGFR) is widely involved in signaling pathways and often deregulated in cancer. Its role in the development of prostate cancer is well established, and therapeutic strategies such as blockade of the intracellular tyrosine kinase domain with small‐molecule tyrosine kinase inhibitors have been proposed. Herein we describe the synthesis and in vitro pharmacological properties of C6‐ and C7‐substituted 4‐anilinoquinazolines, analogues of Iressa and powerful proapoptotic inducers in hormone‐independent prostate cancer PC3 cell lines.

New NSAIDs-NO hybrid molecules with antiproliferative properties on human prostatic cancer cell lines.

The design of profen hybrids containing a NO donor moiety connected to an aliphatic spacer led to compounds with a similar cyclooxygenase inhibition compared to their parent profen and with significant antiproliferative activities on PC3 cells. However, inhibition of COX-2 pathway alone did not seem sufficient to inhibit cancer cell proliferation, and NO-release in a time-dependent manner strongly contributes to this activity.

New analogues of the anticancer E7070: synthesis and pharmacology.

Cell cycle control in the G1 phase has attracted considerable attention in recent cancer research, because many of the important proteins involved in G1 progression or G1/S transition have been found to play a crucial role in proliferation, differentiation, transformation, and programmed cell death (apoptosis). E7070 is a novel antitumor sulfonamide, with a unique mode of action that affects G1 progression of the cell cycle. A series of compounds containing an N-[1-(3,4,5-trimethoxybenzyl)-1H-indol-5-yl]benzene sulfonamide, analogues of E7070, was synthesized and evaluated as potential antitumor agents. Cell cycle analysis with PC3 human prostate cancer cells revealed a cellular accumulation in the G1 phase.