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2.
NPJ Precis Oncol ; 5(1): 98, 2021 Nov 29.
Article in English | MEDLINE | ID: mdl-34845311

ABSTRACT

Cancers harboring mutations in the Kirsten rat sarcoma homolog (KRAS) gene have been associated with poor prognosis and lack of targeted therapies. KRAS mutations occur in approximately one in four patients diagnosed with non-small cell lung cancer (NSCLC) with KRAS G12C mutations harbored at approximately 11-16%. Research into KRAS-driven tumors and analytical chemistry have borne a new class of selective small molecules against the KRAS G12C isoform. Phase II data for sotorasib (AMG510) has demonstrated a 37.1% overall response rate (ORR). Adagrasib (MRTX849) has demonstrated a 45% ORR in an early study. While single agent efficacy has been seen, initial data suggest combination approaches are an opportunity to improve outcomes. Here, we present perspectives on the initial progress in targeting KRAS G12C, examine co-mutations evident in KRAS G12C NSCLC, and comment on potential future combinatorial approaches including SHP2, SOS1, MEK, EGFR, mTOR, CDK, and checkpoint blockade which are currently being evaluated in clinical trials. As of May 28, 2021, sotorasib has achieved US FDA approval for patients with KRAS G12C mutant lung cancer after one line of a prior therapy.

3.
Nature ; 570(7761): 385-389, 2019 06.
Article in English | MEDLINE | ID: mdl-31142840

ABSTRACT

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.


Subject(s)
Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , DNA Fragmentation , Genome, Human/genetics , Neoplasms/diagnosis , Neoplasms/genetics , Case-Control Studies , Cohort Studies , DNA Mutational Analysis , Humans , Machine Learning , Mutation , Neoplasms/blood , Neoplasms/pathology
4.
Cancer Res ; 79(4): 689-698, 2019 02 15.
Article in English | MEDLINE | ID: mdl-30718357

ABSTRACT

EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , ErbB Receptors/antagonists & inhibitors , Humans , Lung Neoplasms/pathology , Prognosis
5.
Cancer Res ; 79(6): 1204-1213, 2019 03 15.
Article in English | MEDLINE | ID: mdl-30573519

ABSTRACT

With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months, P < 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics.Significance: Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment.See related commentary by Zou and Meyerson, p. 1038.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/pathology , Circulating Tumor DNA/analysis , DNA, Neoplasm/analysis , Molecular Targeted Therapy , Mutation , Protein Kinase Inhibitors/therapeutic use , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Circulating Tumor DNA/genetics , DNA, Neoplasm/genetics , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Prognosis , Survival Rate , Tumor Burden
6.
Oncology (Williston Park) ; 32(4): 156-63, 2018 04 15.
Article in English | MEDLINE | ID: mdl-29684234

ABSTRACT

Brain metastases are common in patients with non-small-cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients. Novel compounds for epidermal growth factor receptor-dependent and anaplastic lymphoma kinase-dependent lung cancer have demonstrated blood-brain barrier permeability and have led to important improvements in central nervous system outcomes. Studies of targeted therapies for oncogene-driven tumors and of immunotherapies in patients with brain metastases have shown promise and, allied with novel radiation techniques, are driving a rapid evolution in treatment and prognosis for NSCLC brain metastases.


Subject(s)
Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/secondary , Lung Neoplasms/pathology , Anaplastic Lymphoma Kinase , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Humans , Immunotherapy , Mutation , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
7.
Data Brief ; 15: 724-727, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29124098

ABSTRACT

This dataset provides a shapefile containing approximately 3500 polygons with the location, extent, size, and year of clearcut harvest events occurring between 1984 and 2015 in forested areas of the northern Colorado, Landsat WRS-2 scene Path 034, Row 032. Harvest events were modeled and mapped using a 32 year time series of Landsat imagery, the LandTrendr algorithm, and ancillary datasets. The dataset also conveys information on the elevation, aspect, ownership, distance to roads, and the watershed where each harvest event occurred.

8.
Sci Transl Med ; 9(403)2017 Aug 16.
Article in English | MEDLINE | ID: mdl-28814544

ABSTRACT

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.


Subject(s)
Circulating Tumor DNA/metabolism , Early Detection of Cancer/methods , Neoplasms/diagnosis , Neoplasms/pathology , Blood Cells/metabolism , Case-Control Studies , Cell-Free Nucleic Acids/blood , Circulating Tumor DNA/blood , Disease Progression , Female , Genes, Neoplasm , Humans , Mutation/genetics , Neoplasm Staging , Neoplasms/blood , Neoplasms/genetics , Preoperative Care , Sequence Analysis, DNA , Treatment Outcome
9.
Mol Cancer Ther ; 16(5): 948-955, 2017 05.
Article in English | MEDLINE | ID: mdl-28468865

ABSTRACT

Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Herein, we analyzed cfDNA in the ascites and pleural effusions from six individuals with metastatic cancer. In all cases, cfDNA copy number variations (CNV) were discovered within the effusate. One individual had a relevant alteration with a high copy amplification in EGFR in a never smoker with lung cancer, who showed only MDM2 and CDK4 amplification in a prior tissue biopsy. Another subject with metastatic breast cancer had cytology-positive ascites and an activating PIK3CA mutation identified in the tissue, blood, and ascites collectively. This individual had tumor regression after the administration of the mTOR inhibitor everolimus and had evidence of chromotripsis from chromosomal rearrangements noted in the cell-free ascitic fluid. These results indicate that cfDNA from ascites and pleural effusions may provide additional information not detected with tumor and plasma cell-free DNA molecular characterization, and a context for important insights into tumor biology and clonal dynamic change within primary tumor and metastatic deposits. Mol Cancer Ther; 16(5); 948-55. ©2017 AACR.


Subject(s)
Ascites/genetics , Cell-Free Nucleic Acids/genetics , Genome, Human/genetics , Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Ascites/blood , Cell Line, Tumor , Cell-Free Nucleic Acids/blood , Class I Phosphatidylinositol 3-Kinases/genetics , Cyclin-Dependent Kinase 4/genetics , DNA Copy Number Variations/genetics , ErbB Receptors/genetics , Female , Humans , Male , Middle Aged , Mutation , Neoplasms/blood , Neoplasms/classification , Neoplasms/pathology , Pleural Effusion/genetics , Proto-Oncogene Proteins c-mdm2/genetics
10.
Clin Cancer Res ; 23(16): 4716-4723, 2017 Aug 15.
Article in English | MEDLINE | ID: mdl-28420725

ABSTRACT

Purpose: Noninvasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine.Experimental Design: We tested the hypothesis that dynamic changes in EGFR activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non-small cell lung cancer (NSCLC) patients receiving osimertinib, a second-line third-generation anti-EGFR tyrosine kinase inhibitor.Results: Eight of nine evaluable NSCLC patients had detectable T790M-mutant DNA fragments in pretreatment baseline samples. Daily monitoring of mutations in urine indicated a pattern of intermittent spikes throughout week 1, suggesting apoptosis with an overall decrease in fragment numbers from baselines to day 7 preceding radiographic response assessed at 6 to 12 weeks.Conclusions: These findings suggest drug-induced tumor apoptosis within days of initial dosing. Daily sampling of ctDNA may enable early assessment of patient response and proof-of-concept studies for drug development. The modeling of tumor lysis through the day-to-day kinetics of ctDNA released into the blood and then into the urine is demonstrated in this proof-of-concept study in lung cancer patients receiving anti-EGFR tyrosine kinase inhibitors. This strategy may determine the specific clonal populations of cells which undergo apoptosis within the first week of therapy. This has important implications for developing combinational strategies to address inter- and intralesional heterogeneity and characterizing residual disease after initial drug exposure. Clin Cancer Res; 23(16); 4716-23. ©2017 AACR.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Circulating Tumor DNA/urine , DNA, Neoplasm/urine , Lung Neoplasms/drug therapy , Piperazines/therapeutic use , Acrylamides , Aged , Aniline Compounds , Apoptosis/drug effects , Apoptosis/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/urine , Circulating Tumor DNA/genetics , DNA, Neoplasm/genetics , Drug Monitoring , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Exons/genetics , Humans , Lung Neoplasms/genetics , Lung Neoplasms/urine , Middle Aged , Molecular Targeted Therapy , Mutation , Protein Kinase Inhibitors/therapeutic use , Time Factors , Treatment Outcome
11.
Mol Diagn Ther ; 21(4): 375-384, 2017 08.
Article in English | MEDLINE | ID: mdl-28337711

ABSTRACT

Targeted therapies have changed the treatment landscape of non-small cell lung cancer over the past decade. Analyses of cell free circulating tumor DNA (ctDNA) provide a non-invasive and robust approach for cancer diagnosis and prognosis, real-time monitoring of treatment response, and the identification of appropriate therapeutic targets based on the detection of tumor genetic aberrations. Recent improvements in the sensitivity, specificity, and feasibility of ctDNA detection assays allow the possibility for implementation into clinical practice. This review will focus on key studies using ctDNA analysis in early lung cancer detection, prediction of treatment response, monitoring minimal residual disease and disease relapse, and the identification of resistance mechanisms. We explore how ctDNA can be used as a surrogate for tissue biopsy and an integral biomarker in the clinical management of patients with non-small cell lung cancer.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Circulating Tumor DNA/genetics , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/genetics , Mutation , Neoplasm Proteins/genetics , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/enzymology , Circulating Tumor DNA/blood , Early Detection of Cancer/methods , Gene Expression , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Molecular Targeted Therapy , Neoplasm Proteins/metabolism , Prognosis , Protein Kinase Inhibitors/therapeutic use , Recurrence
12.
Mol Cancer Ther ; 16(2): 265-272, 2017 02.
Article in English | MEDLINE | ID: mdl-28159915

ABSTRACT

The vast majority of patients with metastatic lung cancers who initially benefit from EGFR-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the challenge of treating tumors resistant to EGFR inhibitors. Resistance mechanisms include new, second-site mutations within EGFR (e.g., T790M and C797S), upregulation of MET kinase, upregulation of insulin growth factor receptor (IGFR), HER2 amplification, increased expression of AXL, BIM modulation, NF-κB activation, histologic switch to small-cell cancer, epithelial-to-mesenchymal transition, PDL1 expression with subsequent immune tolerance, and release of cytokines such as TGFß and IL6. Herein, we review the growing body of knowledge regarding EGFR bypass pathways, and the development of new drugs and combination treatment strategies to overcome resistance. Mol Cancer Ther; 16(2); 265-72. ©2017 AACR.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Biomarkers , Carrier Proteins , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/immunology , Cell Transformation, Neoplastic/metabolism , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Molecular Targeted Therapy , Protein Binding , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effects , Tumor Microenvironment
13.
Hematol Oncol Clin North Am ; 31(1): 113-129, 2017 02.
Article in English | MEDLINE | ID: mdl-27912827

ABSTRACT

With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents. This review highlights treatment options, including clinical trials for ROS1 rearrangement, RET fusions, NTRK1 fusions, MET exon skipping, BRAF mutations, and KRAS mutations.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung , Drug Delivery Systems/methods , Lung Neoplasms , Mutation , Neoplasm Proteins , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism
14.
Curr Treat Options Oncol ; 17(5): 25, 2016 May.
Article in English | MEDLINE | ID: mdl-27085533

ABSTRACT

OPINION STATEMENT: Brain metastases are common in patients with non-small cell lung cancer (NSCLC), and due to associated poor prognosis, this field is an important area of need for the development of innovative medical therapies. Therapies including local approaches through surgical intervention and/or radiation and evolving systemic therapies have led to improvements in the treatment of brain metastases in patients with lung cancer. Strategies that consider applying advanced radiation techniques to minimize toxicity, intervening early with effective systemic therapies to spare radiation/surgery, testing radiosensitization combinations, and developing drug penetrant molecules have and will continue to define new practice patterns. We believe that in carefully considered asymptomatic patients, first-line systemic therapy may be considered before radiation therapy and small-molecule targeted therapy may provide an opportunity to defer radiation therapy for recurrence or progression of disease. The next several years in oncology drug development will see the reporting on of brain penetrant molecules in oncogene-defined non-small cell lung cancer. Ongoing studies will evaluate immunotherapies in patients with brain metastases with associated endpoints. We hope that continued drug development and carefully designed clinical trials may afford an opportunity to improve the lives of patients with brain metastases.


Subject(s)
Brain Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/pathology , Animals , Antineoplastic Agents/therapeutic use , Blood-Brain Barrier , Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/secondary , Humans , Immunotherapy , Lung Neoplasms/therapy
15.
Am J Physiol Endocrinol Metab ; 283(6): E1299-307, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12388133

ABSTRACT

Abnormalities in intracellular pH regulation have been proposed to be important in type 2 diabetes and the associated cardiomyopathy and hypertension. We have therefore investigated the dependence of insulin-stimulated glucose transport on cytosolic pH in cardiomyocytes. Insulin treatment of cardiomyocytes resulted in a marked alkalinization of the cytoplasm as measured using carboxy-semi-napthorhodofluor-1. The alkalinizing effect of insulin was blocked by treatment with either cariporide (which inhibits the Na+/H+ exchanger) or by bafilomycin A1 (which inhibits H+-ATPase activity). After treatments with cariporide or bafilomycin A1, insulin stimulation of insulin receptor and insulin receptor substrate-1 phosphorylation and Akt activity were normal. In contrast, glucose transport activity and the levels of functional GLUT4 at the plasma membrane (detected using an exofacial photolabel) were reduced by approximately 50%. Immunocytochemical analysis revealed that insulin treatment caused a translocation of the GLUT4 from perinuclear structures and increased its co-localization with cell surface syntaxin 4. However, neither cariporide nor bafilomycin A1 treatment reduced the translocation of immunodetectable GLUT4 to the sarcolemma region of the cell. It is therefore hypothesized that insulin-stimulated cytosol alkalinization facilitates the final stages of translocation and incorporation of fully functional GLUT4 at the surface-limiting membrane.


Subject(s)
Cytosol/metabolism , Glucose/metabolism , Insulin/pharmacology , Macrolides , Monosaccharide Transport Proteins/metabolism , Muscle Proteins , Myocardium/metabolism , Protein Serine-Threonine Kinases , Animals , Anti-Bacterial Agents/pharmacology , Biological Transport/drug effects , Cell Membrane/metabolism , Cell Nucleus/metabolism , Cytosol/drug effects , Glucose Transporter Type 4 , Guanidines/pharmacology , Hydrogen-Ion Concentration/drug effects , Insulin Receptor Substrate Proteins , Male , Membrane Proteins/metabolism , Myocardium/cytology , Phosphoproteins/metabolism , Phosphorylation/drug effects , Protein Transport/drug effects , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Proton-Translocating ATPases/antagonists & inhibitors , Qa-SNARE Proteins , Rats , Rats, Wistar , Receptor, Insulin/metabolism , Signal Transduction/drug effects , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sulfones/pharmacology
16.
J Mol Cell Cardiol ; 34(5): 509-18, 2002 May.
Article in English | MEDLINE | ID: mdl-12056855

ABSTRACT

TNF alpha administration mimics ischemic preconditioning and neutralizing antibodies to TNF alpha and IL-1 beta abolish exercise-induced preconditioning. However, the pharmacology of TNF alpha's cardioprotective effects and associated downstream signaling events has not been delineated. We evaluated the temporal and dose specific requirements of TNF alpha to function as a preconditioning mimetic. Furthermore we postulated that the preconditioning effect of TNF alpha might be orchestrated via sphingolipid signaling. The cardioprotective effect of TNF alpha and the role of sphingolipid signaling were assessed using a classical preconditioning protocol in the isolated perfused rat heart with the measurement of infarct size and contractile function modulation in response to index ischemia and reperfusion. Recombinant TNF alpha at an optimal dose of 0.5 ng/ml mimicked ischemic preconditioning by reducing infarct size by 60%v non-preconditioned ischemia-reperfusion controls (P<0.01). The infarct sparing effect of TNF alpha required a wash-out period prior to the index ischemic-reperfusion. Moreover, the classic ischemic preconditioning antagonist such as 5-hydroxydecanoate abolished TNF alpha preconditioning. An inhibitor of the sphingolipid signaling pathway, N-oleoylethanolamine (NOE, 1 microm) attenuated ischemic and TNF alpha preconditioning. Likewise, cell-permeable C(2)-ceramide and sphingosine 1-phosphate (sphingolipid signaling intermediates) both reproduced the preconditioning cardioprotective phenotype. Finally, TNF alpha and ceramide conferred preconditioning-like cardioprotection against post-ischemic contractile dysfunction and this cardioprotective effect was attenuated by NOE. In contrast, NOE did not reverse ischemic preconditioning enhanced post-ischemic contractile function. In conclusion, TNF alpha activates preconditioning-like tolerance against infarction and contractile dysfunction. This cardioprotection is mediated, in part, via activation of novel sphingolipid signaling intermediates.


Subject(s)
Ischemic Preconditioning, Myocardial , Myocardial Ischemia/prevention & control , Signal Transduction/physiology , Sphingolipids/metabolism , Tumor Necrosis Factor-alpha/therapeutic use , Animals , Male , Rats , Rats, Long-Evans , Tumor Necrosis Factor-alpha/metabolism , Ventricular Function
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