Current Drug Targets Volume 2, Number 1, 2001

Current Drug Targets Volume 2, Number 1, 2001

Contents

Physiological Roles for K+ Channels and Gap Junctions in Urogenital Smooth Muscle: Implications for Improved Understanding of Urogenital Function, Disease and Therapy Pp. 1-20

Venkateswarlu Karicheti and George J. Christ

Abstract

Chemokine Receptors as Anti-Retroviral Targets Pp. 21-39

Nikolaus Heveker

Abstract

Receptor Tyrosine Kinases as Therapeutic Targets: the Model of the MET Oncogene Pp. 41-55

Paola Longati, Paolo M. Comoglio and Alberto Bardelli

Abstract

Signal Transduction Pathways and Transcriptional Mechanisms as Targets for Prevention of Emergence of Multidrug Resistance in Human Cancer Cells Pp. 57-77

Alexander A. Shtil

Abstract

Discovery and Design of Selective Cyclooxygenase-2 Inhibitors as Non-Ulcerogenic, Anti-Inflammatory Drugs with Potential Utility as Anti-Cancer Agents Pp. 79-106

Amit S. Kalgutkar and Zhiyang Zhao

Abstract

Abstracts

[Back to top] Physiological Roles for K+ Channels and Gap Junctions in Urogenital Smooth Muscle: Implications for Improved Understanding of Urogenital Function, Disease and Therapy

Venkateswarlu Karicheti and George J. Christ

Smooth muscle cells constitute a heterogeneous collection of effector cells that, by virtue of both their constituency in blood vessels and presence as primary parenchymal cells in diverse tissues, affect the function of all organs. Thus, perhaps it is not surprising that alterations in, and/or dysfunction of, smooth muscle cells are quite common, and responsible, at least in part, for the morbidity and mortality associated with a very wide range of human diseases. These facts point to the necessity for improved understanding of the mechanism(s) governing the control of myocyte contractility (i.e., tone). Such understanding has been rapidly forthcoming in recent years, and has indicated that in many smooth muscle cell types intercellular communication through gap junctions acts in concert with nonjunctional (K + ) ion channels to make important contributions to the control of myocyte tone and tissue homeostasis in physiologically diverse organs. Intercellular communication through connexin43-derived gap junction channels and K + flux through the Kca and KATP channel subtypes, in particular, appear to play prominent roles in this process. The goal of this report, therefore, is to review the data concerning junctional and nonjunctional ion channels on the detrusor myocytes of the urinary bladder, as well as on the specialized vascular myocytes of the corpus cavernosum. The choice of an excitable (i.e., bladder detrusor myocytes) and nonexcitable (i.e., corporal smooth muscle) smooth muscle cell type ensures that the discussion will at least encompass consideration of a large portion of the spectrum of physiological possibilities for the participation of junctional and nonjunctional ion channels in the initiation, maintenance and modulation of smooth muscle tone. A central thesis of this communication is that detailed knowledge of the myocyte- and tissue-specific properties of K + channels and gap junctions will likely lead to the improved understanding and treatment of human smooth muscle diseases/disorders.

[Back to top] Chemokine Receptors as Anti-Retroviral Targets

Nikolaus Heveker

The discovery that chemokine receptors act as cofactors indispensable for HIV entry into target cells identified new targets for anti-retroviral therapy. However, much remains to be learned about the nature of their physiological role in the organism, as well as the molecular details of viral entry. The multitude of different receptors permitting HIV entry in vitro and their respective roles in vivo for entry, as well as their implication in distinct pathogenic events have added further complexity to this field of research.

This review summarizes knowledge on HIV-coreceptors, their role under normal physiological conditions as well as in HIV pathogenesis and its implications on the development of concepts for the use of coreceptor targeting therapeutic approaches. An overview over antiviral ligands of chemokine receptors reported so far, as well as alternative strategies of antiviral interventions involving chemokine receptors is given.

[Back to top] Receptor Tyrosine Kinases as Therapeutic Targets: the Model of the MET Oncogene

Paola Longati, Paolo M. Comoglio and Alberto Bardelli

Control of cell growth and differentiation occurs via extracellular signals known as growth factors. Growth factors are high affinity ligands for transmembrane receptors belonging to the family of receptor tyrosine kinases (RTKs).

A number of genetic evidences have implicated RTKs in human diseases including developmental disorders and cancer. For instance, germline missense mutations involving the Ret receptor are found in patients affected by multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) or familial medullary thyroid carcinomas. Somatic mutations in the Kit receptor are found in mastocytomas and in gastrointestinal tumors. Germline and sporadic mutations of the Met receptor have been described in kidney and hepatocellular carcinomas. Overexpression of the HER-2/neu receptor in breast cancer has been associated with tumor progression.

The enzymatic activity of RTKs is strictly regulated and is usually inhibited under basal conditions. Receptor activation triggers a biochemical signalling cascade inside the cytoplasm, named signal transduction, which is subverted during the malignant transformation of cells. Signal transduction by RTKs is a multistep process which includes: (i) Ligand binding and receptor dimerization, (ii) receptor phosphorylation on tyrosine residues; (iii) recruitment to the receptor and activation of cytoplasmic signaling molecules that transmit signals to the nucleus. Each of the steps involved in this process can potentially be targeted to block the aberrant properties of tyrosine kinase receptors. By using the MET oncogene as a model this review focuses on the strategies that can be applied to therapeutically target RTKs.

[Back to top] Signal Transduction Pathways and Transcriptional Mechanisms as Targets for Prevention of Emergence of Multidrug Resistance in Human Cancer Cells

Alexander A. Shtil

Pleiotropic resistance of tumor cells to treatment remains one of the major obstacles for successful cure of cancer patients. Tumor cells may acquire multidrug resistance (MDR) in the course of exposure to various compounds that are used in modern anticancer therapy, including cytotoxic drugs and differentiating agents. Therefore, the recurrence of the disease after the initial treatment may be associated with establishment of secondary MDR in the residual tumor. This phenotype is frequently mediated by P-glycoprotein, an ATP-dependent transmembrane pump capable of effluxing numerous compounds out of the cell. In humans, P-glycoprotein is encoded by the MDR1 gene. Rapid increase of the steady-state level of the MDR1 mRNA in response to stress stimuli is the mechanism of acquisition of P-glycoprotein- mediated MDR in cancer cells. Thus, up-regulation of the MDR1 gene is regarded as part of cellular stress response. This review shows that block of mechanisms that regulate the MDR1 overexpression can prevent the emergence of MDR in tumor cells that expressed null-to-low levels of MDR1 mRNA or P-glycoprotein prior to treatment. In particular, the MDR1 activation can be abrogated by targeting cytoplasmic pathways of signal transduction as well as by interfering with transcriptional up-regulation.

[Back to top] Discovery and Design of Selective Cyclooxygenase-2 Inhibitors as Non-Ulcerogenic, Anti-Inflammatory Drugs with Potential Utility as Anti-Cancer Agents

Amit S. Kalgutkar and Zhiyang Zhao

The recent marketing of two selective cyclooxygenase-2 (COX-2) inhibitors, celecoxib® and rofecoxib® is remarkable considering that COX-2 was only discovered eight years ago as a growth factor- and cytokine-inducible gene. Concomitant with these pharmaceutical successes is the advances in our understanding of the molecular and structural basis for selective COX-2 inhibition. This review provides a perspective on the ongoing structure-activity relationship (SAR) efforts in the search of COX-2-specific inhibitors with particular reference to their structural basis for isozyme-specific inhibition. In addition to the existing inhibitor classes, this review will also highlight many novel structural classes which have recently emerged due to a better understanding of the active site differences between the two isozymes with a special emphasis on the modification of the well-established non-steroidal anti-inflammatory drug (NSAID) scaffold. In addition to its role in inflammation, recent studies suggest that COX-2-derived prostaglandins may play a pivotal part in the maintenance of tumor viability, growth, and metastasis. In this review, we summarize the NSAID epidemiological evidence, studies demonstrating overexpression of COX-2 in multiple human tumors and pharmacological evidence in animal models, which indicate that COX-2 inhibitors could be used in the prevention or treatment of a broader range of disease.