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Drug Resistance Mechanisms (drug + resistance_mechanism)
Selected AbstractsProteome mapping of overexpressed membrane-enriched and cytosolic proteins in sodium antimony gluconate (SAG) resistant clinical isolate of Leishmania donovaniBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010Awanish Kumar WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Over 60% of patients with visceral leishmaniasis (VL) in India and Sudan have become unresponsive to treatment with pentavalent antimonials, the first line of drugs for over 60 years. The drug resistance mechanism, studied so far in in vitro selected laboratory strains, has been attributed to various biochemical parameters. The resistance to Sb (V) in Leishmania field isolates is still unexplored. WHAT THIS STUDY ADDS In order to elucidate for the first time the mechanism of drug resistance in field isolates, this study was done in those clinically relevant field isolates which were either responsive or non responsive to SAG. A comparison of proteome profiles of membrane-enriched as well as cytosolic protein fractions of these isolates has pinpointed the multiple overexpressed proteins in resistant isolates. This study has indicated their possible essential role in antimony resistance of the parasite and provides a vast field to be exploited to find much needed novel treatment strategies against VL. AIMS This study aimed to identify differentially overexpressed membrane-enriched as well as cytosolic proteins in SAG sensitive and resistant clinical strains of L. donovani isolated from VL patients which are involved in the drug resistance mechanism. METHODS The proteins in the membrane-enriched as well as cytosolic fractions of drug-sensitive as well as drug-resistant clinical isolates were separated using two-dimensional gel electrophoresis and overexpressed identified protein spots of interest were excised and analysed using MALDI-TOF/TOF. RESULTS Six out of 12 overexpressed proteins were identified in the membrane-enriched fraction of the SAG resistant strain of L. donovani whereas 14 out of 18 spots were identified in the cytosolic fraction as compared with the SAG sensitive strain. The major proteins in the membrane-enriched fraction were ABC transporter, HSP-83, GPI protein transamidase, cysteine,leucine rich protein and 60S ribosomal protein L23a whereas in the cytosolic fraction proliferative cell nuclear antigen (PCNA), proteasome alpha 5 subunit, carboxypeptidase, HSP-70, enolase, fructose-1,6-bisphosphate aldolase, tubulin-beta chain have been identified. Most of these proteins have been reported as potential drug targets, except 60S ribosomal protein L23a and PCNA which have not been reported to date for their possible involvement in drug resistance against VL. CONCLUSION This study for the first time provided a cumulative proteomic analysis of proteins overexpressed in drug resistant clinical isolates of L. donovani indicating their possible role in antimony resistance of the parasite. Identified proteins provide a vast field to be exploited for novel treatment strategies against VL such as cloning and overexpression of these targets to produce recombinant therapeutic/prophylactic proteins. [source] Evaluating budesonide efficacy in nasal polyposis and predicting the resistance to treatmentCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2009F. C. P. Valera Summary Background Cell resistance to glucocorticoids is a major problem in the treatment of nasal polyposis (NP). Objectives The objectives of this study were to observe the effect of budesonide on the expression of IL-1,, TNF-,, granulocyte macrophage-colony stimulating factor, intercellular adhesion molecule (ICAM)-1, basic fibroblast growth factor, eotaxin-2, glucocorticoid receptor (GR)-,, GR-,, c-Fos and p65 in nasal polyps and to correlate their expression to clinical response. Methods Biopsies from nasal polyps were obtained from 20 patients before and after treatment with topical budesonide. Clinical response to treatment was monitored by a questionnaire and nasal endoscopy. The mRNA levels of the studied genes were measured by real-time quantitative (RQ)-PCR. Results There was a significant decrease in the expression of TNF-, (P<0.05), eotaxin-2 (P<0.05) and p65 (P<0.05) in NP after treatment. Poor responders to glucocorticoids showed higher expression of IL-1, (3.74 vs. 0.14; P<0.005), ICAM-1 (1.91 vs. 0.29; P<0.05) and p65 (0.70 vs. 0.16; P<0.05) before treatment. Following treatment, IL-1, (4.18 vs. 0.42; P<0.005) and GR-, (0.95 vs. 0.28; P<0.05) mRNA expression was higher in this group. Conclusion Topical budesonide reduced the expression of TNF-,, eotaxin-2 and p65. Poor responders to topical budesonide exhibit higher levels of IL-1,, ICAM-1 and nuclear factor (NF)-,B at diagnosis and higher expression of both IL-1, and GR-, after treatment. These results emphasize the anti-inflammatory action of topical budesonide at the molecular level and its importance in the treatment of NP. Nevertheless, IL-1,, ICAM-1 and NF-,B may be associated with primary resistance to glucocorticoids in NP, whereas higher expression of GR-, in poor responders only after glucocorticoid treatment may represent a secondary drug resistance mechanism in this disease. [source] Cell survival and apoptosis-related molecules in cancer cells in effusions: A comprehensive reviewDIAGNOSTIC CYTOPATHOLOGY, Issue 8 2009Lilach Kleinberg Ph.D. Abstract Spreading of cancer cells to effusions is a manifestation of advanced disease, for which the chances of achieving cure using conventional treatment are low. This emphasizes both the importance of improving early detection and the need for developing targeted therapy modes. Such approaches should be based on characterization of the antiapoptotic, survival and drug resistance mechanisms of the metastatic cells in addition to analysis of the primary tumor. This review presents current knowledge regarding the expression and clinical role of cell survival and apoptosis-related molecules in nonhematological cancers in effusions. Differences in the anatomic site-related expression and clinical role of these proteins are additionally discussed. The data presented highlight the complexity of the multiple molecular pathways that mediate tumor cell survival within the serosal cavities. Diagn. Cytopathol. 2009. © 2009 Wiley-Liss, Inc. [source] Systemic therapy for metastatic malignant melanoma , from deeply disappointing to bright future?EXPERIMENTAL DERMATOLOGY, Issue 5 2008Paul Lorigan Abstract:, The last decade has seen a considerable improvement in the understanding of the biology of melanoma. Advances have come in the understanding of the importance of critical oncogenes and tumour suppressor genes, epigenetic phenomena, signalling pathways, drug resistance mechanisms, the pivotal role of the local immune system, and the importance of cell,cell and cell,matrix interactions. Many of these pathways and interactions include potentially ,drugable' targets. These developments have allowed the identification and/or design of a range of new, targeted therapies. Evaluation of these new drugs has brought a whole new series of challenges. These include indentification of appropriate pre-clinical models, overcoming the redundancy inbuilt in complex biological systems, identification of appropriate molecular and clinical endpoints to show that the drug is hitting the target, how to combine treatments, and new toxicities. For the first time, there is the possibility of personalised treatment for melanoma patients, based on individual host and tumour characteristics. This paper discusses the range of new drugs and targets have been identified, the outcome of clinical trials, and the directions for future advances. [source] A Chemical Approach Towards Understanding the Mechanism and Reversal of Drug Resistance in Plasmodium falciparum: Is it Viable?IUBMB LIFE, Issue 4-5 2002Kelly Chibale Abstract Genetic and biochemical approaches to studies of drug resistance mechanisms in Plasmodium falciparum have raised controversies and contradictions over the past several years. A different and novel chemical approach to this important problem is desirable at this point in time. Recently, the molecular basis of drug resistance in P. falciparum has been associated with mutations in the resistance genes, Chloroquine Resistance Transporter (PfCRT) and the P-glycoprotein homologue (Pgh1). Although not the determinant of chloroquine resistance in P. falciparum, mutations in Pgh1 have important implications for resistance to other antimalarial drugs. Because it is mutations in the aforementioned resistance genes rather than overexpression that has been associated with drug resistance in malaria, studies on mechanisms of drug resistance and its reversal by chemosensitisers should benefit from a chemical approach. Target-oriented organic synthesis of chemosensitisers against proteins implicated in drug resistance in malaria should shed light on mechanism of drug resistance and its reversal in this area. The effect of structurally diverse chemosensitisers should be examined on several putative resistance genes in P. falciparum to deal with antimalarial drug resistance in the broadest sense. Therefore, generating random mutations of these resistance proteins and subsequent screening in search of a specific phenotype followed by a search for mutations and/or chemosensitisers that affect a specific drug resistance pathway might be a viable strategy. This diversity-oriented organic synthesis approach should offer the means to simultaneously identify resistance proteins that can serve as targets for therapeutic intervention (therapeutic target validation) and chemosensitisers that modulate the functions of these proteins (chemical target validation). [source] Role of Network Branching in Eliciting Differential Short-Term Signaling Responses in the Hypersensitive Epidermal Growth Factor Receptor Mutants Implicated in Lung CancerBIOTECHNOLOGY PROGRESS, Issue 3 2008Jeremy Purvis We study the effects of EGFR inhibition in wild-type and mutant cell lines upon tyrosine kinase inhibitor TKI treatment through a systems level deterministic and spatially homogeneous model to help characterize the hypersensitive response of the cancer cell lines harboring constitutively active mutant kinases to inhibitor treatment. By introducing a molecularly resolved branched network systems model (the molecular resolution is introduced for EGFR reactions and interactions in order to distinguish differences in activation between wild-type and mutants), we are able to quantify differences in (1) short-term signaling in downstream ERK and Akt activation, (2) the changes in the cellular inhibition EC50 associated with receptor phosphorylation (i.e., 50% inhibition of receptor phosphorylation in the cellular context), and (3) EC50 for the inhibition of activated downstream markers ERK-(p) and Akt-(p), where (p) denotes phosphorylated, upon treatment with the inhibitors in cell lines carrying both wild-type and mutant forms of the receptor. Using the branched signaling model, we illustrate a possible mechanism for preferential Akt activation in the cell lines harboring the oncogenic mutants of EGFR implicated in non-small-cell lung cancer and the enhanced efficacy of the inhibitor erlotinib especially in ablating the cellular Akt-(p) response. Using a simple phenomenological model to describe the effect of Akt activation on cellular decisions, we discuss how this preferential Akt activation is conducive to cellular oncogene addiction and how its disruption can lead to dramatic apoptotic response and hence remarkable inhibitor efficacies. We also identify key network nodes of our branched signaling model through sensitivity analysis as those rendering the network hypersensitive to enhanced ERK-(p) and Akt-(p); intriguingly, the identified nodes have a strong correlation with species implicated in oncogenic transformations in human cancers as well as in drug resistance mechanisms identified for the inhibitors in non-small-cell lung cancer therapy. [source] | |||||||||||||