Current Medicinal Chemistry (v.16, #15)
In Situ Modulation of Oxidative Stress: A Novel and Efficient Strategy to Kill Cancer Cells by J. Verrax, R. Pedrosa, R. Beck, N. Dejeans, H. Taper, P. Calderon (1821-1830).
Cancer cells show an up-regulation of glycolysis, they readily take up vitamin C, and they appear more susceptible to an oxidative stress than the surrounding normal cells. Here we compare, analyse and discuss these particular hallmarks by performing experiments in murine hepatomas (TLT cells) and freshly isolated mouse hepatocytes. The results show that rates of lactate formation are higher in TLT cells as compared to mouse hepatocytes, but their ATP content represents less than 25and#x25; of that in normal cells. The uptake of vitamin C is more important in hepatoma cells as compared to normal hepatocytes. This uptake mainly occurs through GLUT1 transporters. Hepatoma cells have less than 10and#x25; of antioxidant enzyme activities as compared to normal hepatocytes. This decrease includes not only the major antioxidant enzymes, namely catalase, superoxide dismutase and glutathione peroxidase, but also the GSH content. Moreover, catalase is almost not expressed in hepatoma cells as shown by western blot analysis. We explored therefore a selective exposure of cancer cells to an oxidative stress induced by pro-oxidant mixtures containing pharmacological doses of vitamin C and a redox active compound such as menadione (vitamin K3). Indeed, the combination of vitamin C (which accumulates in hepatoma cells) and a quinone undergoing a redox cycling (vitamin K3) leads to an oxidative stress that kills cancer cells in a selective manner. This differential sensitivity between cancer cells and normal cells may have important clinical applications, as it has been observed with other pro-oxidants like Arsenic trioxide, isothiocyanates, Adaphostin.
CDC25A and B Dual-Specificity Phosphatase Inhibitors: Potential Agents for Cancer Therapy by Antonio Lavecchia, Carmen Di Giovanni, Ettore Novellino (1831-1849).
Members of the cell division cycle 25 (Cdc25) family of proteins are highly conserved dual specificity phosphatases, which play a fundamental role in transitions between cell cycle phases during normal cell division through the activation of CdK/cyclin complexes. Furthermore, they are important targets of checkpoints in cellular pathways in the response to DNA damage. Over the past few years, more information about the basic enzymology of the Cdc25 phosphatases has emerged, with the identification of three Cdc25 phosphatase isoforms (A, B, and C) in mammalians. In particular, the Cdc25 A and B phosphatases have oncogenic properties and are overexpressed singly in some types of cancers and together in others. Therefore, it is not surprising that the Cdc25s are interesting targets for the development of new anticancer therapeutic strategies. In this review, we examine the most important classes of reversible inhibitors that show specificity for the Cdc25 A and B phosphatases (both singly and together) and the recent advances in the design of new potent Cdc25 A and B inhibitors. Using computational methodologies, we also consider their plausible mechanisms of action.
Adrenoceptors: Non Conventional Target for Breast Cancer? by I Luthy, A. Bruzzone, C. Pinero, L. Castillo, I. Chiesa, S. Vazquez, M. Sarappa (1850-1862).
Epinephrine and Norepinephrine, typically released during stress bind to nine different adrenoceptors (AR) which classically control the cardiovascular and respiratory systems. New targets were described for the many agonists and antagonists developed for these AR, as the central nervous system. During the last three decades, AR expression and action on the mammary gland/breast were extensively investigated. In the cow mammary gland, good milkability was associated with low density of and#946;2-AR and high density of and#945;2-AR. In the rat normal mammary gland, and#946;-AR are expressed in the epithelial cells, alveoli, ducts, and adipocytes showing an exquisite regulation by steroid hormones and prolactin. In rat dimethylbenz(a)anthracene (DMBA) tumors, a close correlation was observed between tumor growth and and#946;-AR concentration. and#946;2-AR were described in numerous human cell lines and breast tumors. The action of and#946;-adrenergic compounds on cell proliferation is contradictory. While some authors found that and#946;-agonists significantly inhibit cancer cell proliferation and tumor growth in mice, others described a significant reduction in DNA synthesis by and#946;-blockers. Also, positive effects of and#946;-AR on human carcinoma cell migration have been described. and#945;2-AR are expressed in human breast cancer and non-cancer cell lines, their stimulation being associated with increased cell proliferation. In vivo clonidine increased tumor growth and and#945;2-adrenergic antagonists completely reversed this effect. When administered alone, rauwolscine inhibited tumor growth behaving as an inverse agonist. Therefore, the numerous adrenergic and#946;- and and#945;-AR agonists or antagonists could prove to be unexpected therapeutic options for mammary gland/ breast and mainly breast cancer.
Estrogenic Compounds, Estrogen Receptors and Vascular Cell Signaling in the Aging Blood Vessels by Dia Smiley, Raouf Khalil (1863-1887).
The cardiovascular benefits of menopausal hormone therapy (MHT) remain controversial. The earlier clinical observations that cardiovascular disease (CVD) was less common in MHT users compared to non-users suggested cardiovascular benefits of MHT. Also, experimental studies have identified estrogen receptors ERand#945;, ERand#946; and GPR30, which mediate genomic or non-genomic effects in vascular endothelium, smooth muscle, and extracellular matrix (ECM). However, data from randomized clinical trials (RCTs), most notably the Women's Health Initiative (WHI) study, have challenged the cardiovascular benefits and highlighted adverse cardiovascular events with MHT. The discrepancies have been attributed to the design of RCTs, the subjects' advanced age and preexisting CVD, and the form of estrogen used. The discrepancies may also stem from age-related changes in vascular ER amount, distribution, integrity, and post-receptor signaling pathways as well as structural changes in the vasculature. Age-related changes in other sex hormones such as testosterone may also alter the hormonal environment and influence the cardiovascular effects of estrogen. Investigating the chemical properties, structure-activity relationship and pharmacology of natural and synthetic estrogens should improve the effectiveness of conventional MHT. Further characterization of phytoestrogens, selective estrogen-receptor modulators (SERMs), and specific ER agonists may provide substitutes to conventional MHT. Conditions with excess or low estrogen levels such as polycystic ovary syndrome (PCOS) and Turner syndrome may provide insight into the development and regulation of ER and the mechanisms of aberrant estrogen-ER interactions. The lessons learned from previous RCTs have led to more directed studies such as the Kronos Early Estrogen Prevention Study (KEEPS). Careful design of experimental models and RCTs, coupled with the development of specific ER modulators, hold the promise of improving the actions of estrogen in the aging blood vessels and thereby enhancing the efficacy and safety of MHT in postmenopausal CVD.
Pharmacotherapy of Obesity - Benefit, Bias and Hyperbole by Rama Nair, Jun Ren (1888-1897).
Overweight and obesity, if sustained, are serious medical problems reaching an epidemic proportion. It is estimated that over 55and#x25; of the adult population is affected by overweight and obesity. Both overweight and obesity put these individuals at a high risk for the development of insulin resistance, hypertension, dyslipidemia, type 2 diabetes and coronary heart disease. A weight loss of between 5and#x25; and 10and#x25; of the initial body weight has been shown to greatly reduce these health risks associated with overweight and obesity. Typically, the first-line clinical strategy for weight loss is a combination of supervised diet, exercise and behavior modification. Although life style modification can exert beneficial effects in overweighed and obese individuals, it is difficult to achieve and maintain weight losses solely by life style change. Anti-obesity drugs may be used in obese patients (BMI of 30 or greater), or overweight patients with established comorbidities (BMI > 27), where dietary and lifestyle modifications are unsuccessful in achieving a 10and#x25; weight reduction following at least three months of the supervised care. Current anti-obesity drug therapy is geared towards reducing energy/food intake via actions on either gastrointestinal system or the central control of appetite and feeding. A thorough understanding of the molecular pathways involved in weight gain and appetite suppression should help for a better drug design and development. This mini review will focus on the molecular mechanisms and currently available pharmacotherapeutic interventions in overweight and obesity.
New Anti-Tuberculosis Drugs: Strategies, Sources and New Molecules by Juan Palomino, Daniela Ramos, Pedro da Silva (1898-1904).
Tuberculosis is still a major health problem worldwide. Although treatment regimens currently available can cure almost all tuberculosis drug susceptible cases, problems such as the length of treatment, the need for multidrug therapy, the emergence of drug resistance, HIV co-infection and persistent Mycobacterium tuberculosis bacilli, stress the need for new anti-tuberculosis drugs. Strategies to search for new anti-tuberculosis drugs involve: screening libraries of small molecules and natural products or the previous identification of targets crucial to the microorganism and the subsequent design of new molecules. Development of new drugs from known compounds having already shown safety and efficacy is an attractive strategy from the economical, pharmaceutical and clinical point of view. Several derivatives of known molecules and new compounds with different targets have been studied with promising preliminary results. Anti-tuberculosis compounds from natural sources have an enormous potential for the development of new drugs, which have shown not only antimicrobial activity per se but also inhibition of the mechanism of resistance (e.g. efflux pumps) or modulation of the immune response (e.g. macrophage stimulation). If these new drugs are going to have an impact in the treatment of the disease they should ideally be active not only against multiplying microorganisms but also against persistent or dormant bacilli. Due to the complexity of the pathology of M. tuberculosis it is unlikely that a single new drug will be enough. This review will discuss strategies for evaluating drug candidates, new targets, new compounds obtained from synthesis and natural sources, and clinical trials that are currently in progress.
Pertinence of Apoptosis Markers for the Improvement of In Vitro Fertilization (IVF) by D. Haouzi, S. Hamamah (1905-1916).
In assisted reproductive technology (ART), the pregnancy and birth rates following in vitro fertilization (IVF) attempts are still low. Recently, apoptotic markers have been suggested as new criteria for oocyte and embryo quality selection. Many studies have provided evidence that poor oocyte and embryo quality can be associated with apoptosis. The aim of this review is to summarize our current knowledge on the apoptotic process in oocytes and embryos, and focus on the possibility for using apoptotic markers as a reliable and predictive marker to select competent oocytes and embryos during IVF. Moreover, it is currently accepted that IVF failures, linked to poor embryo quality, are, in part, associated with suboptimal in vitro culture conditions. Here, we also review the current state of knowledge concerning how the genetic control of apoptosis during folliculogenesis and pre-implantation embryonic development is affected by in vitro culture conditions during IVF. In the future, identification of apoptotic markers in ART for oocyte and embryo selection should result in the development of new agonistic or antagonistic molecules of apoptosis by medicinal chemistry.
Lithium Pharmacodynamics and Pharmacogenetics: Focus on Inositol Mono Phosphatase (IMPase), Inositol Poliphosphatase (IPPase) and Glycogen Sinthase Kinase 3 Beta (GSK-3 Beta) by Alessandro Serretti, Antonio Drago, Diana De Ronchi (1917-1948).
The mechanisms of lithium action are not known in detail. First messengers, second messengers, and gene expression all appear to be involved: the wide breadth of targets makes the lithium therapeutic path difficult to disentangle. In the present paper, we focused on the most direct biochemical lithium targets at therapeutic concentration, for which some pharmacogenetic finding is present (i.e. inositol mono phosphatase (IMPase), inositol polyphosphate-1-phosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta)). They are all inhibited by lithium at therapeutic concentrations and are representative of the inositol depletion and of the GSK-3 beta based theories of lithium action. Then we surveyed gene variants on those targets that have been associated also with bipolar disorder. On the basis of the molecular characteristics of these proteins, we suggest a set of critical genetic variations. IMPase2, IPPase and GSK-3 beta gene appear to be good candidates for the analysis of lithium prophylactic efficacy and bipolar disorder phenotypes but the genetic association analysis conducted so far reported negative or not unequivocal finding. This may be due to the incomplete coverage of gene mutations in most studies or to the several actions that lithium is thought to perform and trigger in cell machinery, including receptors, calcium equilibrium, gene expression, activation of neuroprotective paths and other yet undetected or less considered mechanisms.