Identification of a small-molecule inhibitor of Stat5a/b through structure-based screen for therapy development for prostate cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 17-17
Author(s):  
Z. Liao ◽  
L. Gu ◽  
F. Shen ◽  
A. Dagvadorj ◽  
S. Gupta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Nuclear Translocation ◽  
Human Prostate ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Molecule Inhibitor ◽  
Prostate Cancers

17 Background: There are no effective treatments for metastatic or castration resistant prostate cancer. We have shown that transcription factor Stat5a/b is constitutively active in high-grade prostate cancer, but not in normal human prostate epithelium. Stat5a/b is active in 95% of clinical castration resistant prostate cancers, and the expression of active Stat5a/b in primary prostate cancer predicts early disease recurrence. Stat5a/b is critical for the viability of prostate cancer cells in vitro and for growth of prostate xenograft tumors in nude mice. Stat5a/b synergizes with androgen receptor (AR) and Stat5a/b promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Here, we hypothesize that Stat5a/b is a molecular target for rational drug design for prostate cancer. Methods: We identified a small- molecule inhibitor of Stat5a/b dimerization by structure-based virtual screen from a database of 30 million chemical structures. The efficacy of the Stat5a/b inhibitor was determined by reporter gene assays, dimerization by co-immunoprecipitations, nuclear translocation by cytochemistry and binding to DNA by EMSA. Cell viability was analyzed by MTT assay. Results: The novel Stat5a/b inhibitor IST5-002 inhibited transcriptional activity of Stat5a/b at IC50 of 1.5 μ M for Stat5a and 3.5 μ M for Stat5b, but not of Stat3 in prostate cancer cells. IST5-002 inhibited dimerization, nuclear translocation, and binding of Stat5a/b to the Stat5 DNA consensus sequence. Furthermore, IST5-002 inhibited expression of Stat5a/b target gene cyclin D1, and induced massive apoptosis of DU145, CWR22Rv1 and LNCaP human prostate cancer cells. IST5-002 blocked prostate cancer xenograft tumor growth in nude mice and induced death in clinical prostate cancers ex vivo in 3D organ cultures. Conclusions: We have identified a small molecule Stat5a/b inhibitor IST5-002 for therapy development for prostate cancer. Future work will focus on chemical modifications of IST5-002 to achieve IC50 below 1 μ M and oral administration. No significant financial relationships to disclose.

Novel biomarker of specific castration-resistant prostate cancer (CRPC) by exploring the proteome analysis.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 247-247 ◽  
Author(s):  
Hiroji Uemura ◽  
Noriaki Arakawa ◽  
Yusuke Itoh ◽  
Takashi Kawahara ◽  
Yasuhide Miyoshi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Proteome Analysis ◽  
Human Prostate ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Prostate Hyperplasia ◽  
Castration Resistant ◽  
Significant Difference ◽  
Prostate Cancers

247 Background: It is well known that prostate specific antigen (PSA) level has no reliable correlation with pathological malignancy of prostate cancer and is not a predictor for the development of castration resistant prostate cancer (CRPC). The aim of this study is to explore novel biomarkers to predict the development of CRPC by using proteomics from secreted proteins from human prostate cancer cells. Methods: The proteins secreted from 6 prostate cancers in culture medium were analyzed and compared with 8 other cancer cells including renal and urothelial cancers using LTQ Orbitrap mass spectrometer. With the focus on high tissue specificity, the candidate biomarker proteins were then identified through analysis of gene expressions in proteins common to human prostate cancers by real time qPCR. Next, a system to measure the identified mouse monoclonal antibodies against the focused proteins was established. Finally, serum levels of these proteins from 33 patients with benign prostate hyperplasia (BPH), 31 with untreated prostate cancer (PCa) and 35 with CRPC, were measured. Results: The proteome analysis identified 12 candidates of secreted cell membrane proteins as new biomarkers. The proteome analysis indicated that not only matured GDF15, but pro-peptide as well as fragments (GDDP) are released from prostate cancer cells. Patients’ serum was analyzed for matured and pro-peptide GDF15 using ELISA and immunoprecipitation-MRM mass spectrometry. The results showed that the serum level of GDDP-1, one of the processing forms of GDDP, was significantly higher in CRPC than those in BPH and untreated PCa (P < 0.01). ROC analysis also showed that the AUC of GDDP-1(0.86) was higher than that of matured GDF15 (0.76). When the cutoff value of GDDP-1 was set at 4.0 ng/mL, there was a significant difference of overall survival (OS) in CRPC patients between those with more than 4.0 ng/mL compared to less than 4.0 ng/mL of GDDP-1, whereas there was no significant difference of OS measurable by PSA in CRPC patients. These data suggest that GDDP-1 may be a novel biomarker for CRPC. Conclusions: GDDP-1 shows potential as a novel biomarker for CRPC.

scholarly journals Activating Mutation (V617F) in the Tyrosine Kinase JAK2 is Absent in Locally-Confined or Castration-Resistant Prostate Cancer

2010 ◽  
Vol 33 (2) ◽  
pp. 55-59 ◽  
Author(s):  
Lei Gu ◽  
Xian-Hua Zhu ◽  
Tapio Visakorpi ◽  
Kalle Alanen ◽  
Tuomas Mirtti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Activating Mutation ◽  
Prostate Cancers

Background: Transcription factor Stat5a/b is highly critical for the viability of human prostate cancer cells in vitro and for prostate tumor growthin vivo. Stat5 is constitutively active in clinical prostate cancers but not in the normal human prostate epithelium. Moreover, Stat5a/b activation in prostate cancer is associated with high histological grade of prostate cancer. However, the molecular mechanisms underlying constitutive activation of Stat5a/b in prostate cancer are unclear. The receptor-associated tyrosine kinase Jak2 is a known key activator of Stat5a/b in prostate cancer cells in response to ligand stimulation. Recently, a single gain-of-function point mutation ofJAK2was described in myeloproliferative diseases leading to constitutive Jak2 kinase activity, subsequent Stat5a/b activation and involvement of V617F Jak2 in the pathogenesis of myeloproliferative disorders.Materials and Methods: We determined whetherJAK2undergoes the V617F activating mutation during clinical progression of human prostate cancer using a highly sensitive assay (amplification refractory mutation system) and a unique material of fresh specimens from organ-confined or castration-resistant prostate cancers.Results: TheJAK2V617F mutation was not found in any of the normal or malignant prostate samples analyzed in this study.Conclusions: Future work should focus on determining the molecular mechanisms other than V617F mutation of Jak2 resulting in continuous Stat5 activation in clinical prostate cancers.

Blueberry flavonoids inhibit matrix metalloproteinase activity in DU145 human prostate cancer cells

2005 ◽  
Vol 83 (5) ◽  
pp. 637-643 ◽  
Author(s):  
Michael D Matchett ◽  
Shawna L MacKinnon ◽  
Marva I Sweeney ◽  
Katherine T Gottschall-Pass ◽  
Robert A.R Hurta
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Human Prostate ◽  
Response To Treatment ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
The Matrix ◽  
Ecm Degradation

Regulation of the matrix metalloproteinases (MMPs), the major mediators of extracellular matrix (ECM) degradation, is crucial to regulate ECM proteolysis, which is important in metastasis. This study examined the effects of 3 flavonoid-enriched fractions (a crude fraction, an anthocyanin-enriched fraction, and a proanthocyanidin-enriched fraction), which were prepared from lowbush blueberries (Vaccinium angustifolium), on MMP activity in DU145 human prostate cancer cells in vitro. Using gelatin gel electrophoresis, MMP activity was evaluated from cells after 24-hr exposure to blueberry fractions. All fractions elicited an ability to decrease the activity of MMP-2 and MMP-9. Of the fractions tested, the proanthocyanidin-enriched fraction was found to be the most effective at inhibiting MMP activity in these cells. No induction of either necrotic or apoptotic cell death was noted in these cells in response to treatment with the blueberry fractions. These findings indicate that flavonoids from blueberry possess the ability to effectively decrease MMP activity, which may decrease overall ECM degradation. This ability may be important in controlling tumor metastasis formation.Key words: blueberry flavonoids, MMP activity, prostate cancer cells.

scholarly journals Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 711 ◽  
Author(s):  
Haneen Amawi ◽  
Noor Hussein ◽  
Sai H. S. Boddu ◽  
Chandrabose Karthikeyan ◽  
Frederick E. Williams ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Nuclear Translocation ◽  
Wide Spectrum ◽  
Thiophene Ring ◽  
Mitotic Catastrophe ◽  
Prostate Cancer Cells

Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC50 < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.

scholarly journals Identification of genes required for enzalutamide resistance in castration-resistant prostate cancer cells in vitro

2020 ◽  
pp. molcanther.0244.2020
Author(s):  
Sarah E Kohrt ◽  
Wisam N Awadallah ◽  
Robert A Phillips ◽  
Thomas C. Case ◽  
Renjie Jin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant
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