Gefitinib and bicalutamide show synergistic effects in primary cultures of prostate cancer derived from androgen-dependent naive patients

Festuccia, Claudio; Gravina, Giovanni Luca; Muzi, Paola; Biordi, Leda; Ronchi, Piero; Martella, Oreste; Vicentini, Carlo; Bologna, Mauro

doi:10.3892/or.18.5.1321

Cited by 8 publications

(5 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One study found that gefitinib and bicalutamide showed synergistic effects in primary cultures of prostate cancer derived from androgen-dependent naive patients [ 53 ]. Another study discovered that gefitinib-trastuzumab combination showed promising clinical activity in hormone refractory prostate cancer [ 54 ].…”

Section: Case Studiesmentioning

confidence: 99%

IPAD: the Integrated Pathway Analysis Database for Systematic Enrichment Analysis

Zhang

Drabier

2012

BMC Bioinformatics

View full text Add to dashboard Cite

BackgroundNext-Generation Sequencing (NGS) technologies and Genome-Wide Association Studies (GWAS) generate millions of reads and hundreds of datasets, and there is an urgent need for a better way to accurately interpret and distill such large amounts of data. Extensive pathway and network analysis allow for the discovery of highly significant pathways from a set of disease vs. healthy samples in the NGS and GWAS. Knowledge of activation of these processes will lead to elucidation of the complex biological pathways affected by drug treatment, to patient stratification studies of new and existing drug treatments, and to understanding the underlying anti-cancer drug effects. There are approximately 141 biological human pathway resources as of Jan 2012 according to the Pathguide database. However, most currently available resources do not contain disease, drug or organ specificity information such as disease-pathway, drug-pathway, and organ-pathway associations. Systematically integrating pathway, disease, drug and organ specificity together becomes increasingly crucial for understanding the interrelationships between signaling, metabolic and regulatory pathway, drug action, disease susceptibility, and organ specificity from high-throughput omics data (genomics, transcriptomics, proteomics and metabolomics).ResultsWe designed the Integrated Pathway Analysis Database for Systematic Enrichment Analysis (IPAD, http://bioinfo.hsc.unt.edu/ipad), defining inter-association between pathway, disease, drug and organ specificity, based on six criteria: 1) comprehensive pathway coverage; 2) gene/protein to pathway/disease/drug/organ association; 3) inter-association between pathway, disease, drug, and organ; 4) multiple and quantitative measurement of enrichment and inter-association; 5) assessment of enrichment and inter-association analysis with the context of the existing biological knowledge and a "gold standard" constructed from reputable and reliable sources; and 6) cross-linking of multiple available data sources.IPAD is a comprehensive database covering about 22,498 genes, 25,469 proteins, 1956 pathways, 6704 diseases, 5615 drugs, and 52 organs integrated from databases including the BioCarta, KEGG, NCI-Nature curated, Reactome, CTD, PharmGKB, DrugBank, PharmGKB, and HOMER. The database has a web-based user interface that allows users to perform enrichment analysis from genes/proteins/molecules and inter-association analysis from a pathway, disease, drug, and organ.Moreover, the quality of the database was validated with the context of the existing biological knowledge and a "gold standard" constructed from reputable and reliable sources. Two case studies were also presented to demonstrate: 1) self-validation of enrichment analysis and inter-association analysis on brain-specific markers, and 2) identification of previously undiscovered components by the enrichment analysis from a prostate cancer study.ConclusionsIPAD is a new resource for analyzing, identifying, and validating pathway, disease, drug, organ specificity...

show abstract

Section: Case Studiesmentioning

confidence: 99%

IPAD: the Integrated Pathway Analysis Database for Systematic Enrichment Analysis

Zhang

Drabier

2012

BMC Bioinformatics

View full text Add to dashboard Cite

show abstract

“…For example, in MDA PCa 2a prostate cancer cells, the AR antagonist hydroxyflutamide proved more efficacious when combined with cetuximab and trastuzumab [126]. Significantly, in androgen-dependent PCa cell lines, co-administration of gefitinib and bicalutamide resulted in concurrent inhibition of AR and ErbB1/ErbB2 pathways, causing a significant delay in the onset of ErbB-driven castration resistance [127]. The same principle has been suggested for PCa patients who have undergone radical prostatectomy and radiation therapy - lapatinib plus an anti-androgen appear to offer a better therapeutic option than lapatinib alone 2 .…”

Section: Erbb3 and Tki Resistancementioning

confidence: 99%

Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block

Jathal¹,

Chen²,

Mudryj³

et al. 2011

IEMAMC

View full text Add to dashboard Cite

Most prostate cancers (PCa) are critically reliant on functional androgen receptor (AR) signaling. At its onset, PCa is androgen-dependent and although temporarily halted by surgically or pharmacologically blocking the AR (androgen ablation), the disease ultimately recurs as an aggressive, fatal castration resistant prostate cancer (CRPC). FDA-approved treatments like docetaxel, a chemotherapeutic agent, and Provenge, a cancer vaccine, extend survival by a scant 3 and 4 months, respectively. It is clear that more effective drugs targeting CRPC are urgently needed. The ErbB family (EGFR/ErbB1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) of receptor tyrosine kinases (RTKs) have long been implicated in PCa initiation and progression, but inhibitors of ErbB1 and ErbB2 (prototypic family members) fared poorly in PCa clinical trials. Recent research suggests that another family member ErbB3 abets emergence of the castration-resistant phenotype. Considerable efforts are being directed towards understanding ErbB3-mediated molecular mechanisms of castration resistance and searching for novel ways of inhibiting ErbB3 activity via rational drug design. Antibody-based therapy that prevents ligand binding to ErbB3 appears promising and fully-humanized antibodies that inhibit ligand-induced phosphorylation of ErbB3 are currently in early development. Small molecule tyrosine kinase inhibitors are also being vigorously pursued, as are siRNA-based approaches and combination treatment strategies- the simultaneous suppression of ErbB3 and its signaling partners or downstream effectors – with the primary purpose of undermining the resiliency of ErbB3-mediated signal transduction. This review summarizes the existing literature and reinforces the importance of ErbB3 as a therapeutic target in the clinical management of prostate cancer.

show abstract

“…The concomitant increament in the EGFR and Her2 expression synergizes with the reduction of PTEN in the upmodulation of Akt activity. Further we have previously demonstrated that the EGFR inhibitor, gefitinib, is able to synergize with BCLT in AR-positive cell lines in vitro (35,36) and that effectiveness of this treatment regimens was modulated by PTEN/Akt activity. In addition we have also demonstrated that inhibition of PI3K-dependent signaling alone induces proliferative arrest (26).…”

Section: Discussionmentioning

confidence: 96%

Epigenetic modulation of PTEN expression during antiandrogenic therapies in human prostate cancer

Gravina

Biordi²,

Martella³

et al. 2009

Int J Oncol

View full text Add to dashboard Cite

Abstract. Although the tumor-suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is frequently mutated or deleted in a wide variety of solid tumors, some malignancies, including prostate cancer, exhibit undetectable PTEN protein without loss of PTEN gene. Aim of this study was to evaluate whether the PTEN downmodulation, observed during bicalutamide treatment, was due to epigentic events. We analyzed the expression of PTEN in presence or absence of azacitidine or valproic acid in a panel of 50 primary cultures derived from naive (UNT, 23 ptz) and bicalutamide-based neoadjuvant hormone therapy-treated patients (NHT, 27 pts). Results showed that Western blot and PCR analyses showed that 54 and 68% of primary cultures displayed detectable amounts of PTEN protein and mRNA, respectively. Treatment with azacitidine increased the percentage of PTEN-positive cultures up to 72 and 80% for PTEN protein and mRNA determination, respectively. Treatment with valproic acid was able to increase the percentage of PTEN-positive cultures up to 80 and 74% for PTEN protein and mRNA determination, respectively. The percentage of cultures with undetectable levels of PTEN protein was significatively higher in cultures derived NHT patients respect to cultures derived from UNT men (P=0.020). Valproic acid reduced significantly the percentage of cultures PTEN-negative only at protein level and only in NHT (P=0.029) group. In conclusion, our data suggests that antiandrogenic therapy reduced PTEN expression by epigenetic mechanisms suggesting that epigenetic drugs, upmodulating PTEN expression, can reduce Akt activity and probably enhance the efficacy of antiandrogenic therapy.

show abstract

Gefitinib and bicalutamide show synergistic effects in primary cultures of prostate cancer derived from androgen-dependent naive patients

Cited by 8 publications

References 28 publications

IPAD: the Integrated Pathway Analysis Database for Systematic Enrichment Analysis

IPAD: the Integrated Pathway Analysis Database for Systematic Enrichment Analysis

Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block

Epigenetic modulation of PTEN expression during antiandrogenic therapies in human prostate cancer

Contact Info

Product

Resources

About