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Song Li

Publications and source records attributed to Song Li.

At least 19 recordsLinked to original sources
PubMed2026

MYC-bound enhancer RNAs in cis regulate gene transcription and tumorigenesis.

Emerging evidence suggests that MYC binds RNAs, but its functional consequences remain unclear. Here, we integrate multiomics data and reveal that MYC broadly binds enhancer RNAs (eRNAs), which exhibit high cancer- and tissue-specific expression in cancer cell lines and patient tumors. Moreover, we developed a computational pipeline to identify potential cis-regulatory MYC-eRNA target genes, with most predicted eRNA-target pairs supported by RNA polymerase II-mediated chromatin interaction data. Among these, we functionally characterized MERG1 as an oncogenic eRNA that promotes breast cancer tumorigenesis. Mechanistically, MERG1 interacts with MYC to enhance its occupancy at the GREB1 promoter, driving chromatin remodeling and epigenetic activation. This process specifically amplifies GREB1 expression and promotes tumor progression. Last, nanoparticle-mediated delivery of antisense oligonucleotides targeting MERG1 suppresses MYC-mediated breast cancer growth. These results advance our understanding of the enhancer-driven regulation of gene expression and tumorigenesis and provide insights into the regulatory landscape of MYC in cancer.

Humans↗
PubMed2025

Transcriptome sequencing reveals regulatory genes associated with neurogenic hearing loss.

Hearing loss is a prevalent condition with a significant impact on individuals' quality of life. However, comprehensive studies investigating the differential gene expression and regulatory mechanisms associated with hearing loss are lacking, particularly in the context of diverse patient samples. In this study, we integrated data from 10 patients across different regions, age groups, and genders, with their data retrieved from a public transcriptome database, to explore the molecular basis of hearing loss. These samples are mainly from fibroblasts and keratinocytes. Through differential gene expression analysis, we identified key genes, including ICAM1, SLC1A1, and CD24, which have already been shown to play important roles in neurogenic hearing loss. Furthermore, we predicted potential transcriptional regulatory factors that may modulate the expression of these genes. Enrichment analysis revealed biological processes and pathways associated with hearing loss, highlighting the involvement of circadian rhythm disruption and other neuro-related disorders. Although our study is limited by the sample size and the absence of larger-scale investigations, the identified genes and regulatory factors provide valuable insights into the molecular mechanisms underlying hearing loss. Further molecular and cellular experiments are necessary to validate these findings and elucidate the precise regulatory mechanisms involved. In conclusion, our study contributes to the understanding of hearing loss pathogenesis and offers potential targets for molecular diagnostics and gene-based therapies. This provides a foundation for further research into personalized approaches to diagnosing and treating hearing loss.

Humans↗
PubMed2006

Augmented suppression of androgen receptor signaling by a combination of alpha-tocopheryl succinate and methylseleninic acid.

BACKGROUND: Previous reports showed that alpha-tocopheryl succinate (alphaTS) and methylseleninic acid (MSA) independently reduce the abundance of androgen receptor (AR) in prostate cancer cells. The response to MSA happens quickly, whereas the response to alphaTS takes much longer. The present study was designed to investigate whether a combination of alphaTS and MSA would produce an additive or a greater than additive effect in suppressing AR level, AR transactivation, and prostate-specific antigen (PSA). METHODS: LNCaP cells were treated with alphaTS alone for 31 hours, MSA alone for 3 hours, or alphaTS first for 28 hours and alphaTS/MSA together for the last 3 hours. AR and PSA mRNA levels were quantitated by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). AR transactivation was determined by the ARE-luciferase reporter assay. Both cellular and secretory PSA was also measured by the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Different doses of alphaTS were evaluated in combination with MSA. Some striking results are highlighted below for alphaTS alone, MSA alone, or alphaTS/MSA (presented in that order). AR mRNA level was depressed by 0%, 20%, or 60%, respectively; AR transactivation was inhibited by 35%, 10%, or 60%, respectively; whereas the PSA mRNA level was decreased by 40%, 60%, or 90%, respectively. Interestingly, secretory PSA was consistently reduced to a greater extent than cellular PSA. CONCLUSIONS: A combination of alphaTS/MSA produced a greater than additive effect in suppressing AR signaling compared with the single agent. Decreased AR abundance is a major factor, but not necessarily the sole factor, in diminishing the transcriptional activity of AR by alphaTS or MSA.

Androgen Receptor Antagonists↗
PubMed2006

Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.

BACKGROUND: BRCA1 and BRCA2 mutations in general populations and in various types of cancers have not been well characterized. We investigated the presence of these mutations in unselected patients with newly diagnosed incident ovarian cancer in Ontario, Canada, with respect to cancers reported among their relatives. METHODS: A population series of 1171 unselected patients with incident ovarian cancer diagnosed between January 1, 1995, and December 31, 1999, in Ontario, Canada, was screened for germline mutations throughout the BRCA1 and BRCA2 genes. Screening involved testing for common variants, then protein truncation testing of long exons, and then denaturing gradient gel electrophoresis or denaturing high-performance liquid chromatography for the remainder of BRCA1 and BRCA2, respectively. Cox regression analysis was used to examine cancer outcomes reported by the case probands for their 8680 first-degree relatives. Population allele frequencies and relative risks (RRs) were derived from the regression results by an extension of Saunders-Begg methods. Age-specific Ontario cancer incidence rates were used to estimate cumulative incidence of cancer to age 80 years by mutation status. RESULTS: Among 977 patients with invasive ovarian cancer, 75 had BRCA1 mutations and 54 had BRCA2 mutations, for a total mutation frequency of 13.2% (95% confidence interval [CI] = 11.2% to 15.5%). Higher risks for various cancer types in the general Ontario population were associated with BRCA1 mutation carriage than with noncarriage, including ovarian (RR = 21, 95% CI = 12 to 36), female breast (RR = 11, 95% CI = 7.5 to 15), and testis (RR = 17, 95% CI = 1.3 to 230) cancers. Higher risks were also associated with BRCA2 mutation carriage than with noncarriage, particularly for ovarian (RR = 7.0, 95% CI = 3.1 to 16), female and male breast (RR = 4.6, 95% CI = 2.7 to 7.8, and RR = 102, 95% CI = 9.9 to 1050, respectively), and pancreatic (RR = 6.6, 95% CI = 1.9 to 23) cancers. Cancer risks differed according to the mutation's position in the gene. Estimated cumulative incidence to age 80 years among women carrying BRCA1 mutations was 24% for ovarian cancer and 90% for breast cancer and among women carrying BRCA2 mutations was 8.4% for ovarian cancer and 41% for breast cancer. For the general Ontario population, estimated carrier frequencies of BRCA1 and BRCA2 mutations, respectively, were 0.32% (95% CI = 0.23% to 0.45%) and 0.69% (95% CI = 0.43% to 1.10%). CONCLUSIONS: BRCA1 and BRCA2 mutations may be more frequent in general populations than previously thought and may be associated with various types of cancers.

Breast Neoplasms↗
PubMed2006

Glucose and lipid metabolism in small-for-gestational-age infants at 72 hours of age.

CONTEXT: Reduced birth weight is associated with increased risk for the insulin resistance syndrome. Part of this risk is hypothesized to originate from intrauterine growth retardation. OBJECTIVE: The aim of this study is to determine whether or not the components of the insulin resistance syndrome are associated with reduced fetal growth. DESIGN: This was a case-control study. SETTING: The study was conducted in Beijing, China. PARTICIPANTS: Included in this study were 296 singleton neonates (177 males and 119 females), including 76 (37 preterm and 39 full-term newborns) classified as small for gestational age (SGA) and 220 who were appropriate for gestational age (AGA) (84 preterm and 136 full-term newborns). MAIN OUTCOME MEASURES: The main outcome measures were postabsorptive glucose, insulin, and lipids levels on the third day after birth. RESULTS: Both full-term and preterm SGA neonates had higher insulin concentrations (mean +/- SEM, 17.11 +/- 1.15 vs.6.80 +/- 0.62 microIU/ml in full-term, P < 0.01; 11.99 +/- 1.18 vs.8.37 +/- 0.78 microIU/ml in preterm, P = 0.03), insulin to glucose ratios (4.48 +/- 0.37 vs. 1.78 +/- 0.20 in full-term, P < 0.01; 3.28 +/- 0.38 vs. 2.30 +/- 0.26 in preterm, P = 0.03), triglycerides (2.29 +/- 0.23 vs.1.57 +/- 0.13 mmol/liter in full-term, P < 0.01; 2.27 +/- 0.16 vs. 1.34 +/- 0.11 mmol/liter in preterm, P < 0.01), total cholesterol (2.35 +/- 0.12 vs. 1.82 +/- 0.22 mmol/liter in full-term, P = 0.04; 2.57 +/- 0.22 vs. 1.95 +/- 0.15 mmol/liter in preterm, P = 0.02), and low-density lipoprotein cholesterol (2.11 +/- 0.58 vs. 1.24 +/- 0.61 mmol/liter in full-term, P = 0.01; 1.87 +/- 0.60 vs. 1.38 +/- 0.59 mmol/liter in preterm, P < 0.01) concentrations than did AGA neonates; however, they had similar glucose levels. Among AGA infants, insulin concentration, insulin to glucose ratios, and lipids levels did not significantly differ between full-term and preterm babies. CONCLUSIONS: In this study, SGA neonates displayed profiles suggestive of lower insulin sensitivity and less favorable lipid metabolism in the early postnatal period.

Blood Glucose↗
PubMed2006

Prevalence of BRCA1 and BRCA2 mutations in breast cancer patients from Brazil.

The contribution of BRCA1 and BRCA2 to breast cancer incidence in Brazil has not yet been explored. In order to estimate the proportion of breast cancers due to BRCA1 and BRCA2 mutations in Brazil, we conducted a study of unselected breast cancer patients from Rio de Janeiro, Brazil. We enrolled 402 women with breast cancer from a large public hospital and two private medical clinics in the city. A detailed family history was obtained from each patient and a blood sample was obtained for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques, but all mutations were confirmed by direct sequencing. Overall, nine mutations were identified (six in BRCA1 and three in BRCA2) representing 2.3% of the total. The most common mutation, 5382insC in BRCA1, was seen five times and accounted for 56% of all identified mutations. A second mutation, in BRCA2 (6633del5) was seen in two unrelated women. In summary, BRCA1 and BRCA2 mutations are not uncommon in Brazilian women with breast cancer. It appears that a small number of founder mutations may be predominant. Moreover, a small number of founder mutations may be prevalent in Brazil, raising the possibility that a rapid and inexpensive genetic test may be developed to screen for inherited susceptibility to breast cancer in Brazil.

Adult↗
PubMed2006

Anisotropic mechanosensing by mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are a potential source for the construction of tissue-engineered vascular grafts. However, how vascular mechanical forces regulate the genetic reprogramming in MSCs is not well understood. Mechanical strain in the vascular wall is anisotropic and mainly in the circumferential direction. We have shown that cyclic uniaxial strain on elastic substrates causes the cells to align perpendicularly to the strain axis, which is different from that in the vascular wall. To simulate the vascular cell alignment and investigate the anisotropic mechanical sensing by MSCs, we used soft lithography to create elastomeric membranes with parallel microgrooves. This topographic pattern kept MSCs aligned parallel to the strain axis, and the cells were subjected to 5% cyclic uniaxial strain (1 Hz) for 2-4 days. DNA microarray analysis revealed global gene expression changes, including an increase in the smooth muscle marker calponin 1, decreases in cartilage matrix markers, and alterations in cell signaling (e.g., down-regulation of the Jagged1 signaling pathway). In addition, uniaxial strain increased MSC proliferation. However, when micropatterning was used to align cells perpendicularly to the axis of mechanical strain, the changes of some genes were diminished, and MSC proliferation was not affected. This study suggests that mechanical strain plays an important role in MSC differentiation and proliferation, and that the effects of mechanotransduction depend on the orientation of cells with respect to the strain axis. The differential cellular responses to the anisotropic mechanical environment have important implications in cardiovascular development, tissue remodeling, and tissue engineering.

Actins↗
PubMed2006

The effects of chronic valproate and diazepam in a mouse model of posttraumatic stress disorder.

To better understand neurochemical and psychopharmacological aspects of post-traumatic stress disorder (PTSD), it is necessary establish an animal model of PTSD in which behavioral changes persist for a long time after the initial traumatization. The present study aimed to characterize long-term behavioral alterations in male ICR mice as an animal model of PTSD consisting of a 2-day foot shock (0.8 mA, 10 s) followed by 3 weekly situational reminders (SR), and to evaluate the effects of repeated administration of valproate and diazepam on behavioral deficits of this animal model. The results showed that the aversive procedure induced several long-term behavioral deficiencies: increased freezing behavior and anxiety level, reduced time spent in an aversive like context. Repeated treatment with valproate (100-400 mg/kg, i.p.) induced a dose-dependent reduction of these behavioral changes. In contrast, diazepam at a low dose (0.25 mg/kg) but not at a high dose (4 mg/kg) reduced the behavioral deficiencies. These results demonstrate that exposure to intense foot shock associated with repeated situational reminders elicits long-term disturbances that last about 4 weeks after the foot shock exposure. These behavioral deficits can be ameliorated by repeated administration of valproate or diazepam at some special dose ranges.

Animals↗
PubMed2006

FK506-binding protein ligands: structure-based design, synthesis, and neurotrophic/neuroprotective properties of substituted 5,5-dimethyl-2-(4-thiazolidine)carboxylates.

Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand 1 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate) in complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited positive effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. Compound 18 (3-(3-pyridyl)-1-propyl (2S)-5,5-dimethyl-1-(3,3-dimethyl-1,2-dioxobutyl)-2-(4-thiazolidine)carboxylate) afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, 18 at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clinical potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson's disease.

Animals↗
PubMed2006

Potent inhibition of the CD4-dependent T cell response by J2, a novel nonpeptide organic ligand of CD4 D1.

The interaction between CD4 and major histocompatibility complex (MHC) class II proteins is critical for the activation of CD4+ T cells, which are involved in transplantation reactions and a number of autoimmune diseases. It is known that the CD4 N-terminal immunoglobulin variable region-like domain (D1) is directed toward and reaching into the two membrane-proximal domains of the MHC class II molecule. Thus, compounds targeted to D1 would be expected to function as the inhibitors of the interaction of CD4 and class II MHC molecules. In this study, we used a computer-based design method to screen thousands of non-peptidic compounds in a molecular database and identified a group of compounds as potential ligands of CD4 D1. These small organic compounds were then synthesized and tested by actual biological assays. One of them, named J2, which possessed favorable activity, was obtained. Experimental data showed that J2 could specifically block stable CD4-MHC class II binding and elicit significant inhibition of immune responses in vitro and in vivo. All the results demonstrated the therapeutic potential of this compound as a novel immunosuppressive agent.

Acrylamides↗
PubMed2006

Modeling and synthesis of non-cyclic derivatives of GPI-1046 as potential FKBP ligands with neurotrophic properties.

Prompted by the therapeutic potential of the neuroimmunophilin FK506-binding protein (FKBP) ligand, GPI-1046, in the treatment of nerve injuries and neurodegenerative diseases, a novel series of non-cyclic derivatives of GPI-1046 were designed and synthesized. Computer modeling analysis revealed that these relatively linear derivatives could energy-favorably bind to FKBP12 with an analogous binding mode to GPI-1046. The neurotrophic activity of the target compounds was assessed in chick dorsal root ganglion (DRG) cultures. As a result, 6 out of 11 test compounds at either or both concentrations of 1 pM and 100 pM significantly promoted neurite outgrowth in DRGs in the presence of 0.15 ng/ml nerve growth factor (NGF). Compound 5c at 100 pM exhibited the greatest neurotrophic effect in promoting both the number and length of neurite processes. However, in the absence of exogenously added NGF, all test compounds, including GPI-1046, failed to afford any positive effect on DRGs. This study suggests the intriguing potential of these compounds for further investigation.

Animals↗
PubMed2006

A novel dual peroxisome proliferator-activated receptors alpha and gamma agonist with beneficial effects on insulin resistance and lipid metabolism.

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are key regulators of lipid homeostasis and insulin resistance. In this study we show that a novel compound, 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}- 2-[2-(2-nitro-phenoxy)-acetyl amino]-propionic acid (O325H), is an agonist with dual effect on PPARalpha/gamma by using dual-luciferase reporter gene assay. By activating PPARalpha and PPARgamma simultaneously, O325H promotes pre-adipocyte differentiation and up-regulates the expression of glucose and lipid metabolic target genes. In diabetic mice, administration of O325H at 10 mg/kg decreases the blood lipid and glucose levels. Therefore, O325H has dual action on PPARalpha and PPARgamma and is a promising agent for the amelioration of lipid metabolic disorders and diabetes associated with insulin resistance.

Adipocytes↗
PubMed2006

Variable contribution of the MTHFR C677T polymorphism to non-syndromic cleft lip and palate risk in China.

Non-syndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common craniofacial malformations among newborn infants. It has been demonstrated that periconceptional folic acid supplementation may reduce the occurrence of offspring with clefts, particularly in the North China; however, the mechanism remains unknown. Our study of a thermolabile polymorphism (C677T) of methylenetetrahydrofolate reductase (MTHFR) gene in 170 Chinese case-parent triads revealed a moderate association between this MTHFR polymorphism and nsCL/P in a population from North China, but not in a population from South China. Moreover, the study revealed that the heterozygous parents in the North were about twice as likely to transmit the high-risk T allele to affected cases, as that observed in the South (OR = 2.24, 95% CI: 1.08-4.65). Thus, the MTHFR polymorphism is a significant risk factor for nsCL/P in this Northern Chinese population. Our study suggested possible genetic heterogeneity in the development of nsCL/P among Northern and Southern populations in China.

Adult↗
PubMed2006

An automatic variational level set segmentation framework for computer aided dental X-rays analysis in clinical environments.

An automatic variational level set segmentation framework for Computer Aided Dental X-rays Analysis (CADXA) in clinical environments is proposed. Designed for clinical environments, the segmentation contains two stages: a training stage and a segmentation stage. During the training stage, first, manually chosen representative images are segmented using hierarchical level set region detection. Then the window based feature extraction followed by principal component analysis (PCA) is applied and results are used to train a support vector machine (SVM) classifier. During the segmentation stage, dental X-rays are classified first by the trained SVM. The classifier provides initial contours which are close to correct boundaries for three coupled level sets driven by a proposed pathologically variational modeling which greatly accelerates the level set segmentation. Based on the segmentation results and uncertainty maps that are built based on a proposed uncertainty measurement, a computer aided analysis scheme is applied. The experimental results show that the proposed method is able to provide an automatic pathological segmentation which naturally segments those problem areas. Based on the segmentation results, the analysis scheme is able to provide indications of possible problem areas of bone loss and decay to the dentists. As well, the experimental results show that the proposed segmentation framework is able to speed up the level set segmentation in clinical environments.

Algorithms↗
PubMed2006

Establishment of a cell model based on FKBP12 dimerization for screening of FK506-like neurotrophic small molecular compounds.

FK506 is an efficient immunosuppressive agent with an increasing number of clinical applications. It has been approved to prevent rejection in transplant patients and be efficacious in several autoimmune diseases. Its immunosuppressive activity results from binding to receptor proteins designated as immunophilins (i.e., FKBP12, FK506 binding protein). Recent studies have suggested that FK506 can promote neurite outgrowth as a 2nd activity. Furthermore, it has been shown that the neurotrophic property of FK506 is independent of its immunosuppressive action. Although the mechanism of its neurotrophic activity has not yet been well elucidated, FKBP12 is identified as a drug target, and much effort has been directed toward the design of FKBP12-binding molecules, which are neurotrophic but non-immunosuppressive, for clinical use. In this present study, the authors constructed a stable cell line, which underwent apoptosis upon treatment by AP20187, a wholly synthesized, cell-permeable dimeric FK506 derivative, based on FKBP12-mBax dimerization. This AP20187-mediated apoptosis was rapidly reversed by the addition of an FKBP12-binding competitor molecule (FK506 or rapamycin), indicating that this cell line might be used to screen FK506 derivatives. Using the screening model, hundreds of synthetic FK506 analogs were analyzed. A promising compound, named N308, was obtained. The results showed that N308 could inhibit AP20187-induced gene-modified target cell apoptosis and elicit augmentation of neurite extension from both cultured PC-12 cells and chicken dorsal root ganglia cultures.

Animals↗
PubMed2006

Control of cell adhesion on poly(methyl methacrylate).

Keratoprostheses have been constructed from a wide variety of transparent materials, including poly(methyl methacrylate) (PMMA). However, the success of keratoprosthesis has been plagued by numerous shortcomings that include the weakening of the implant-host interface due to weak cell adhesion and opaque fibrous membrane formation over the inner surface of the implant due to fibroblast attachment. An effective solution requires a surface modification that would selectively allow enhanced cell attachment at the implant-host interface and reduced cell attachment over the interior surface of the implant. Here, we have developed a novel and simple peptide conjugation scheme to modify PMMA surfaces, which allowed for region-specific control of cell adhesion. This method uses di-amino-PEG, which can be grafted onto PMMA using hydrolysis or aminolysis method. PEG can resist cell adhesion and protein adsorption. The functionalization of grafted di-amino-PEG molecules with RGD peptide not only restored cell adhesion to the surfaces, but also enhanced cell attachment and spreading as compared to untreated PMMA surfaces. Long-term cell migration and micropatterning studies clearly indicated that PEG-PMMA surfaces with and without RGD conjugation can be used to differentiate cell adhesion and control cell attachment spatially on PMMA, which will have potential applications in the modification of keratoprostheses.

Actins↗
PubMed2006

Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis.

Coexpression of the epidermal growth factor receptor (EGFR) family receptors is found in a subset of colon cancers, which may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. Recently, efforts have been made to develop novel 4-anilinoquinazoline and pyridopyrimidine derivatives to inhibit EGFR and ErbB2 kinases simultaneously. In this study, we tested the efficacy of a novel reversible dual inhibitor GW572016 compared with the selective EGFR and ErbB2 tyrosine kinase inhibitors (TKI) AG1478 and AG879 and their combination, using the human colon adenocarcinoma GEO mode. GEO cells depend on multiple ErbB receptors for aberrant growth. A synergistic effect on inhibition of cell proliferation associated with induction of apoptosis was observed from the combination of AG1478 and AG879. Compared with AG1478 or AG879, the single TKI compound GW572016 was a more potent inhibitor of GEO cell proliferation and was able to induce apoptosis at lower concentrations. Western blot analysis revealed that AG1478 and AG879 were unable to suppress both EGFR and ErbB2 activation as well as the downstream mitogen-activated protein kinase (MAPK) and AKT pathways as single agents. In contrast, GW572016 suppressed the activation of EGFR, ErbB2, MAPK, and AKT in a concentration-dependent manner. Finally, in vivo studies showed that GW572016 treatment efficiently blocked GEO xenograft growth at a dose range of 30 to 200 mg/kg with a twice-daily schedule. In summary, our study indicates that targeting both EGFR and ErbB2 simultaneously could enhance therapy over that of single agents directed at EGFR or ErbB2 in cancers that can be identified as being primarily heterodimer-dependent.

Animals↗