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1.
J Toxicol Sci ; 46(3): 99-114, 2021.
Article in English | MEDLINE | ID: mdl-33642521

ABSTRACT

Microphysiological systems (MPS) are making advances to provide more standardized and predictive physiologically relevant responses to test articles in living tissues and organ systems. The excitement surrounding the potential of MPS to better predict human responses to medicines and improving clinical translation is overshadowed by their relatively slow adoption by the pharmaceutical industry and regulators. Collaboration between multiorganizational consortia and regulators is necessary to build an understanding of the strengths and limitations of MPS models and closing the current gaps. Here, we review some of the advances in MPS research, focusing on liver, intestine, vascular system, kidney and lung and present examples highlighting the context of use for these systems. For MPS to gain a foothold in drug development, they must have added value over existing approaches. Ideally, the application of MPS will augment in vivo studies and reduce the use of animals via tiered screening with less reliance on exploratory toxicology studies to screen compounds. Because MPS support multiple cell types (e.g. primary or stem-cell derived cells) and organ systems, identifying when MPS are more appropriate than simple 2D in vitro models for understanding physiological responses to test articles is necessary. Once identified, MPS models require qualification for that specific context of use and must be reproducible to allow future validation. Ultimately, the challenges of balancing complexity with reproducibility will inform the promise of advancing the MPS field and are critical for realization of the goal to reduce, refine and replace (3Rs) the use of animals in nonclinical research.


Subject(s)
Drug Development/methods , Drug Development/trends , Microfluidic Analytical Techniques , Models, Biological , Animals , Biological Products , Drug Industry , Forecasting , Humans , Lab-On-A-Chip Devices
2.
Toxicol Pathol ; 48(8): 994-1007, 2020 12.
Article in English | MEDLINE | ID: mdl-33252024

ABSTRACT

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.


Subject(s)
Chemical and Drug Induced Liver Injury , Fatty Liver , Metabolic Syndrome , Animals , Diet, High-Fat/adverse effects , Fatty Liver/chemically induced , Humans , Liver , Metabolic Syndrome/chemically induced , Rats , Rats, Sprague-Dawley , Rats, Zucker
3.
Nucleic Acids Res ; 42(8): 4882-91, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24550163

ABSTRACT

Fully phosphorothioate antisense oligonucleotides (ASOs) with locked nucleic acids (LNAs) improve target affinity, RNase H activation and stability. LNA modified ASOs can cause hepatotoxicity, and this risk is currently not fully understood. In vitro cytotoxicity screens have not been reliable predictors of hepatic toxicity in non-clinical testing; however, mice are considered to be a sensitive test species. To better understand the relationship between nucleotide sequence and hepatotoxicity, a structure-toxicity analysis was performed using results from 2 week repeated-dose-tolerability studies in mice administered LNA-modified ASOs. ASOs targeting human Apolipoprotien C3 (Apoc3), CREB (cAMP Response Element Binding Protein) Regulated Transcription Coactivator 2 (Crtc2) or Glucocorticoid Receptor (GR, NR3C1) were classified based upon the presence or absence of hepatotoxicity in mice. From these data, a random-decision forest-classification model generated from nucleotide sequence descriptors identified two trinucleotide motifs (TCC and TGC) that were present only in hepatotoxic sequences. We found that motif containing sequences were more likely to bind to hepatocellular proteins in vitro and increased P53 and NRF2 stress pathway activity in vivo. These results suggest in silico approaches can be utilized to establish structure-toxicity relationships of LNA-modified ASOs and decrease the likelihood of hepatotoxicity in preclinical testing.


Subject(s)
Oligonucleotides, Antisense/toxicity , Oligonucleotides/toxicity , Animals , Liver/drug effects , Liver/pathology , Male , Mice , NF-E2-Related Factor 2/metabolism , Nucleotide Motifs , Oligonucleotides/chemistry , Oligonucleotides/metabolism , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/metabolism , Proteins/metabolism , Tumor Suppressor Protein p53/metabolism
4.
Toxicol Sci ; 138(1): 234-48, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24336348

ABSTRACT

Development of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice administered non-toxic and toxic LNA gapmers. After repeated administration, a toxic LNA gapmer (TS-2), but not a non-toxic LNA gapmer (NTS-1), caused hepatocyte necrosis and increased serum alanine aminotransferase levels. Microarray data revealed that, in addition to gene expression patterns consistent with hepatotoxicity, 17 genes in the clathrin-mediated endocytosis (CME) pathway were altered in the TS-2 group. TS-2 significantly down-regulated myosin 1E (Myo1E), which is involved in release of clathrin-coated pits from plasma membranes. To map the earliest transcription changes associated with LNA gapmer-induced hepatotoxicity, a second microarray analysis was performed using NTS-1, TS-2, and a severely toxic LNA gapmer (HTS-3) at 8, 16, and 72 h following a single administration in mice. The only histopathological change observed was minor hepatic hypertrophy in all LNA groups across time points. NTS-1, but not 2 toxic LNA gapmers, increased immune response genes at 8 and 16 h but not at 72 h. TS-2 significantly perturbed the CME pathway only at 72 h, while Myo1E levels were decreased at all time points. In contrast, HTS-3 modulated DNA damage pathway genes at 8 and 16 h and also modulated the CME pathway genes (but not Myo1E) at 16 h. Our results may suggest that different LNAs modulate distinct transcriptional genes and pathways contributing to non-target mediated hepatotoxicity in mice.


Subject(s)
Chemical and Drug Induced Liver Injury/pathology , Endocytosis/drug effects , Liver/drug effects , Oligonucleotides, Antisense/toxicity , Oligonucleotides/toxicity , Transcriptome/drug effects , Animals , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/genetics , Clathrin/metabolism , Endocytosis/genetics , Gene Expression Profiling , Injections, Subcutaneous , Liver/pathology , Male , Mice , Mice, Inbred Strains , Molecular Sequence Data , Oligonucleotides/chemistry , Oligonucleotides/genetics , Oligonucleotides/metabolism , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/metabolism
5.
Curr Protoc Toxicol ; Chapter 14: Unit 14.11, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23408193

ABSTRACT

Primary hepatocyte sandwich cultures are useful for a variety of research applications where maintenance of metabolic competency is essential. To ensure an optimal hepatocellular phenotype, cells are seeded on collagen-coated dishes and embedded with an overlay of Matrigel. This culturing condition makes gene silencing by traditional reagent-mediated transfection methods challenging. Here, an siRNA delivery method in primary mouse hepatocytes that allows cells to be cultured with Matrigel overlay is described. This method delivers >80% mRNA silencing with minimal alterations in cell viability. A 96-well format allows for high-throughput RNA processing and downstream quantitative PCR applications and reduces time and resources. This format is particularly useful when experiments requiring many different sampling conditions (such as pharmacologic dose-response curves) are required.


Subject(s)
Gene Silencing , Hepatocytes/metabolism , High-Throughput Screening Assays/methods , Primary Cell Culture/methods , RNA, Messenger/genetics , RNA, Small Interfering , Transfection/methods , Animals , Cells, Cultured , Mice , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction
6.
Mol Ther ; 20(9): 1737-49, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22735378

ABSTRACT

The hepatitis C virus (HCV) chronically infects 2% of the world population and effective treatment is limited by long duration and significant side-effects. Here, we describe a novel drug, intended as a "single-shot " therapy, which expresses three short hairpin RNAs (shRNAs) that simultaneously target multiple conserved regions of the HCV genome as confirmed in vitro by knockdown of an HCV replicon system. Using a recombinant adeno-associated virus (AAV) serotype 8 vector for delivery, comprehensive transduction of hepatocytes was achieved in vivo in a nonhuman primate (NHP) model following a single intravenous injection. However, dose ranging studies performed in 13 NHP resulted in high-expression levels of shRNA from wild-type (wt) Pol III promoters and dose-dependent hepatocellular toxicity, the first demonstration of shRNA-related toxicity in primates, establishing that the hepatotoxicity arises from highly conserved features of the RNA interference (RNAi) pathway. In the second generation drug, each promoter was re-engineered to reduce shRNA transcription to levels that circumvent toxicity but still inhibit replicon activity. In vivo testing of this modified construct in 18 NHPs showed conservation of hepatocyte transduction but complete elimination of hepatotoxicity, even with sustained shRNA expression for 50 days. These data support progression to a clinical study for treatment of HCV infection.


Subject(s)
Genome, Viral , Hepacivirus/genetics , Hepatitis C, Chronic/therapy , Hepatocytes/virology , Liver/virology , RNA, Small Interfering/genetics , RNA, Viral/antagonists & inhibitors , Animals , DNA Polymerase III/genetics , Dependovirus/genetics , Genetic Engineering , Genetic Therapy , Genetic Vectors , Hepatitis C, Chronic/virology , Hepatocytes/pathology , Injections, Intravenous , Liver/pathology , Macaca fascicularis , Mice , Promoter Regions, Genetic , RNA, Viral/genetics , Replicon , Transduction, Genetic , Virus Replication
7.
EMBO J ; 26(15): 3686-98, 2007 Aug 08.
Article in English | MEDLINE | ID: mdl-17641685

ABSTRACT

The peroxisome proliferator-activated receptor-beta (PPARbeta) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb(-/-) mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb(-/-) mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57(Kip2) as a PPARbeta target gene and a mediator of the PPARbeta-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb(-/-) mice. Our data point to an unexpected essential role for PPARbeta in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.


Subject(s)
Down-Regulation , Neoplasms, Experimental/blood supply , Neovascularization, Pathologic , PPAR-beta/physiology , Animals , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor p57/metabolism , Endothelium, Vascular/pathology , Magnetic Resonance Imaging , Mice , Mice, Knockout , Neoplasms, Experimental/pathology , Oligonucleotide Array Sequence Analysis , PPAR-beta/genetics , PPAR-beta/metabolism
8.
Cell Signal ; 19(6): 1163-71, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17254750

ABSTRACT

The functional role of peroxisome proliferator-activated receptor-beta(PPARbeta; also referred to as PPARdelta) in epidermal cell growth remains controversial. Recent evidence suggests that ligand activation of PPARbeta/delta increases cell growth and inhibits apoptosis in epidermal cells. In contrast, other reports suggest that ligand activation of PPARbeta/delta leads to the induction of terminal differentiation and inhibition of cell growth. In the present study, the effect of the highly specific PPARbeta/delta ligand GW0742 on cell growth was examined using a human keratinocyte cell line (N/TERT-1) and mouse primary keratinocytes. Ligand activation of PPARbeta/delta with GW0742 prevented cell cycle progression from G1 to S phase and attenuated cell proliferation in N/TERT-1 cells. Despite specifically activating PPARbeta/delta as revealed by target gene induction, no changes in PTEN, PDK and ILK expression or downstream phosphorylation of Akt were found in either N/TERT-1 cells or primary keratinocytes. Further, altered cell growth resulting from serum withdrawal and the induction of caspase-3 activity by ultraviolet radiation were unchanged in the absence of PPARbeta/delta expression and/or the presence of GW0742. While no changes in the expression of mRNAs encoding cell cycle control proteins were found in response to GW0742, a significant decrease in the level of ERK phosphorylation was observed. Results from these studies demonstrate that ligand activation of PPARbeta/delta does not lead to an anti-apoptotic effect in either human or mouse keratinocytes, but rather, leads to inhibition of cell growth likely through the induction of terminal differentiation.


Subject(s)
Keratinocytes/cytology , Keratinocytes/drug effects , PPAR delta/metabolism , PPAR-beta/metabolism , Telomerase/metabolism , Thiazoles/pharmacology , 3-Phosphoinositide-Dependent Protein Kinases , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Differentiation/drug effects , Cell Line , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Gene Expression Regulation/drug effects , Humans , Keratinocytes/enzymology , Keratinocytes/radiation effects , Ligands , MAP Kinase Signaling System/drug effects , Mice , PTEN Phosphohydrolase/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcriptional Activation , Ultraviolet Rays
9.
Carcinogenesis ; 27(11): 2331-40, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16774943

ABSTRACT

Polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (BaP), are known mammary carcinogens in rodents and may be involved in human breast cancer. The carcinogenicity of BaP has been partially attributed to the formation of the BaP diol epoxide (BPDE), which has been shown to stably bind DNA and act as an initiator. BaP is a complete carcinogen, but the mechanisms for tumor promotion are less well characterized. Previous studies have demonstrated that BPDE enhanced anti-apoptotic signaling through Akt; however, mechanisms for Akt activation by BPDE are not well defined. In the current studies, we found that BPDE increased intracellular Ca2+ concentration in the human mammary epithelial cell line MCF-10A. A peak in Ca2+ concentration at 20 min was followed by increased phosphorylation of Pyk2 at Tyr881 and increased total tyrosine phosphorylation of the epidermal growth factor receptor (EGFR). Consistent with activation of the EGFR, Akt and ERK1/2 phosphorylation was detected in MCF-10A cells treated with BPDE. Pharmacological methods to prevent Ca2+ elevation and EGFR activity, and small-interfering RNA against Pyk2, prevented Akt phosphorylation by BPDE, which suggested that Ca2+, Pyk2 and EGFR activation lay upstream of Akt. In addition, we found that BPDE increased p53 activity and apoptosis in MCF-10A; however, transient transfection of constitutively active Akt attenuated both BPDE-dependent apoptosis and p53 activity. In contrast, apoptosis was enhanced by inhibitors of phosphatidyl inositol 3-kinase (PI3-K). This work demonstrates a novel mechanism for Akt activation by BPDE that occurs through increased Ca2+ concentration, and implicates Ca2+, Pyk2, EGFR and Akt as a potential pathway by which BPDE can inhibit apoptosis and act as a promoter of carcinogenesis.


Subject(s)
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide , Apoptosis , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Carcinogens , Focal Adhesion Kinase 2/physiology , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Proto-Oncogene Proteins c-akt/metabolism , Calcium/metabolism , Cell Line, Tumor , Humans , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Signal Transduction , p38 Mitogen-Activated Protein Kinases/metabolism
10.
Cell Signal ; 18(1): 9-20, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16109478

ABSTRACT

The physiological and pharmacological roles of peroxisome proliferator-activated receptor-beta (PPARbeta-also referred to as PPARdelta) are just beginning to emerge. It has recently become clear that PPARbeta has a function in epithelial tissues, but controversy exists due to inconsistencies in the literature. There is strong evidence that ligand activation of PPARbeta can induce terminal differentiation of keratinocytes, with a concomitant inhibition of cell proliferation. However, the role of PPARbeta in keratinocyte-specific apoptosis is less clear. Additionally, the role of PPARbeta in colonic epithelium remains unclear due to conflicting evidence suggesting that ligand activation of PPARbeta can potentiate, as well as attenuate, intestinal cancer. Recent studies revealed that ligand activation of PPARbeta can induce fatty acid catabolism in skeletal muscle and is associated with improved insulin sensitivity, attenuated weight gain and elevated HDL levels thus demonstrating promising potential for targeting PPARbeta for treating obesity, dyslipidemias and type 2 diabetes. Therefore, it becomes critical to determine the safety of PPARbeta ligands. This review focuses on recent literature describing the role of PPARbeta in epithelial tissues and highlights critical discrepancies that need to be resolved for a more comprehensive understanding of how this receptor modulates epithelial homeostasis.


Subject(s)
Epithelial Cells/physiology , Neoplasms/immunology , PPAR delta/physiology , PPAR-beta/physiology , Animals , Cell Differentiation/physiology , Cell Proliferation , Epithelial Cells/metabolism , Homeostasis/physiology , Humans , Neoplasms/chemically induced , Signal Transduction/physiology
11.
Toxicol Sci ; 90(2): 269-95, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16322072

ABSTRACT

Peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors that modulate target gene expression in response to endogenous and exogenous ligands. Ligands for the PPARs have been widely developed for the treatment of various diseases including dyslipidemias and diabetes. While targeting selective receptor activation is an established therapeutic approach for the treatment of various diseases, a variety of toxicities are known to occur in response to ligand administration. Whether PPAR ligands produce toxicity via a receptor-dependent and/or off-target-mediated mechanism(s) is not always known. Extrapolation of data derived from animal models and/or in vitro models, to humans, is also questionable. The different toxicities and mechanisms associated with administration of ligands for the three PPARs will be discussed, and important data gaps that could increase our current understanding of how PPAR ligands lead to toxicity will be highlighted.


Subject(s)
Ligands , Peroxisome Proliferator-Activated Receptors , Animals , Drug-Related Side Effects and Adverse Reactions , Humans
12.
Cancer Res ; 63(22): 7825-33, 2003 Nov 15.
Article in English | MEDLINE | ID: mdl-14633709

ABSTRACT

Polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP), are known mammary carcinogens in rodents and may be involved in human breast cancer. We have reported previously that BaP can mimic growth factor signaling and increase cell proliferation in primary human mammary epithelial cells and the human mammary epithelial cell line MCF-10A. BaP-quinones (BPQs) are important metabolites of BaP that have been associated with the production of reactive oxygen species. Using a model of epidermal growth factor (EGF) withdrawal in MCF-10A, we hypothesized that production of reactive oxygen species by BPQs could lead to the activation of the EGF receptor (EGFR). Here, we demonstrate through electron paramagnetic resonance spectroscopy and flow cytometry that 1,6-BPQ and 3,6-BPQ produce superoxide anion and hydrogen peroxide in MCF-10A cells. Furthermore, we show that BPQs increase EGFR, Akt, and extracellular signal-regulated kinase activity, leading to increased cell number in the absence of EGF. The BPQ-induced EGFR activity and associated cell proliferation were attenuated by the EGFR inhibitor AG1478, as well as by the antioxidant N-acetyl cysteine. Overexpression of catalase, but not Cu/Zn superoxide dismutase, reduced the extent of BPQ-dependent increased cell number and EGFR pathway activation. Moreover, the direct treatment of MCF-10A cells with hydrogen peroxide enhanced EGFR, Akt, and extracellular-regulated kinase phosphorylation that could be similarly inhibited by AG1478, N-acetyl cysteine, and catalase. Taken together, these data indicate that BPQs, through the generation of hydrogen peroxide, activate the EGFR in MCF-10A cells, leading to increased cell number under EGF-deficient conditions.


Subject(s)
Benzopyrenes/toxicity , Breast/drug effects , Breast/metabolism , ErbB Receptors/metabolism , Protein Serine-Threonine Kinases , Reactive Oxygen Species/metabolism , Breast/cytology , Breast Neoplasms/chemically induced , Breast Neoplasms/metabolism , Cell Count , Cell Division/drug effects , Electron Spin Resonance Spectroscopy , Enzyme Activation/drug effects , Epidermal Growth Factor/deficiency , Flow Cytometry , Humans , Hydrogen Peroxide/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/metabolism , Oxidative Stress , Phosphorylation/drug effects , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Signal Transduction/physiology , Transcriptional Activation
13.
Toxicol Appl Pharmacol ; 188(1): 42-9, 2003 Apr 01.
Article in English | MEDLINE | ID: mdl-12668121

ABSTRACT

Previous studies have demonstrated that 2,3,7,8 tetracholorodibenzo-p-dioxin (TCDD) mimics epidermal growth factor receptor (EGFR) signaling in the MCF-10A human mammary epithelial cell line and protects cells from EGF withdrawal-induced apoptosis. These effects appear to be due to the ability of TCDD to increase the expression of transforming growth factor-alpha (TGFalpha), a known EGFR ligand. Because TCDD's effects occurred at concentrations as low as 1 nM, a role for the aryl hydrocarbon receptor (AhR) was hypothesized. In the present study, 3'methoxy-4'nitroflavone (MNF), a known AhR antagonist, was used to analyze AhR signaling in this cell line. MNF suppressed TCDD-dependent dioxin response element (DRE)-driven luciferase activity at concentrations as low as 10 nM. In addition, MNF attenuated TCDD's ability to inhibit apoptosis and to activate Akt and Erk1,2, two EGFR-dependent signaling molecules. Finally, the TCDD-dependent increase in TGFalpha mRNA was also suppressed by MNF. MNF's effects on TCDD action in the MCF-10A cell line occurred at concentrations ranging from 1 nM for Akt phosphorylation and TGFalpha expression to 100 nM for inhibition of apoptosis. Attenuation of TCDD-dependent luciferase activity occurred at concentrations as low as 10 nM, which suggests that TCDD inhibits apoptosis in human mammary epithelial cells by multiple mechanisms.


Subject(s)
Apoptosis/drug effects , Flavonoids/pharmacology , Polychlorinated Dibenzodioxins/toxicity , Protein Serine-Threonine Kinases , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Signal Transduction/drug effects , Transforming Growth Factor alpha/biosynthesis , Cell Line , Epithelial Cells/drug effects , Epithelial Cells/metabolism , ErbB Receptors/metabolism , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt
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