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1.
Oncol Lett ; 16(5): 6437-6444, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30405781

ABSTRACT

Glycogen Synthase Kinase-3ß (GSK-3ß), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. The objective of the present study was to evaluate aberrant expression of GSK-3ß as a potential biomarker in human breast and head and neck cancers. Nuclear/cytosolic fractionation, immunoblotting and immunohistochemical staining was used to study the expression of GSK-3ß in human breast and head and neck cancer. Aberrant nuclear accumulation of GSK-3ß in five human breast cancer cell lines was demonstrated and in 89/128 (70%) human breast carcinomas, whereas no detectable expression of GSK-3ß was found in benign breast tissue. Nuclear GSK-3ß expression was associated with HER-2 positive tumors (P=0.02) and non-triple negative breast carcinomas (P=0.0001), although nuclear GSK-3ß was observed in some samples across all breast cancer subtypes. Aberrant nuclear expression of GSK-3ß was found in 11/15 (73%) squamous cell head and neck carcinomas, whereas weak or no detectable expression of GSK-3ß was found in benign salivary gland and other benign head and neck tissues. These results support the hypothesis that aberrant nuclear GSK-3ß may represent a potential target for the clinical treatment of human breast and squamous cell carcinoma.

2.
Anticancer Drugs ; 29(8): 717-724, 2018 09.
Article in English | MEDLINE | ID: mdl-29846250

ABSTRACT

Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3ß expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.


Subject(s)
Enzyme Inhibitors/pharmacology , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Indoles/pharmacology , Maleimides/pharmacology , Neuroblastoma/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Growth Processes/drug effects , Cell Line, Tumor , Drug Synergism , Female , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Indoles/administration & dosage , Irinotecan/administration & dosage , Irinotecan/pharmacology , Maleimides/administration & dosage , Mice , Mice, Nude , Neuroblastoma/enzymology , Neuroblastoma/pathology , Xenograft Model Antitumor Assays
3.
Proc Natl Acad Sci U S A ; 110(7): 2511-6, 2013 Feb 12.
Article in English | MEDLINE | ID: mdl-23345442

ABSTRACT

New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape. Like natural HDLs, biomimetic HDL-NPs target scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Functionally, compared with natural HDL, the gold NP template enables differential manipulation of cellular cholesterol flux in lymphoma cells, promoting cellular cholesterol efflux and limiting cholesterol delivery. This combination of scavenger receptor type B-1 binding and relative cholesterol starvation selectively induces apoptosis. HDL-NP treatment of mice bearing B-cell lymphoma xenografts selectively inhibits B-cell lymphoma growth. As such, HDL-NPs are biofunctional therapeutic agents, whose mechanism of action is enabled by the presence of a synthetic nanotemplate. HDL-NPs are active in B-cell lymphomas and potentially, other malignancies or diseases of pathologic cholesterol accumulation.


Subject(s)
Biomimetics/methods , Lipoproteins, HDL/therapeutic use , Lymphoma, B-Cell/drug therapy , Metal Nanoparticles/therapeutic use , Animals , Annexin A5 , Apoptosis/physiology , Blotting, Western , Fluorescein-5-isothiocyanate , Humans , Immunoblotting , Jurkat Cells , Lipoproteins, HDL/metabolism , Mass Spectrometry , Mice , Microscopy, Electron, Transmission , Scavenger Receptors, Class B/metabolism
4.
Biochem Biophys Res Commun ; 423(3): 490-5, 2012 Jul 06.
Article in English | MEDLINE | ID: mdl-22683636

ABSTRACT

Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzenesulfonates/therapeutic use , Carcinoma, Renal Cell/drug therapy , Glycogen Synthase Kinase 3/administration & dosage , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Animals , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Renal Cell/enzymology , Cell Proliferation/drug effects , Humans , Kidney Neoplasms/enzymology , Mice , Niacinamide/analogs & derivatives , Phenylurea Compounds , Sorafenib , Xenograft Model Antitumor Assays
5.
Biochem Biophys Res Commun ; 422(4): 607-14, 2012 Jun 15.
Article in English | MEDLINE | ID: mdl-22609199

ABSTRACT

We investigated a prognostic significance and the mechanism of aberrant nuclear expression of EZH2, a histone methyltransferase, in human renal cell carcinoma (RCC). We found nuclear EZH2 in 48 of 100 RCCs and it was significantly correlated with worse survival in RCC patients. We detected a decreased expression of miR-101 in 15 of 54 RCCs. We found that re-expression of miR-101 resulted in EZH2 depletion and decreased renal cancer cell proliferation. Our results show nuclear EZH2 as a prognostic marker of worse survival in human RCC, and identify miR-101 as a negative regulator of EZH2 expression and renal cancer cell proliferation.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , DNA-Binding Proteins/genetics , Enhancer Elements, Genetic , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , MicroRNAs/metabolism , Transcription Factors/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/mortality , Cell Nucleus/metabolism , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor p27/genetics , DNA-Binding Proteins/metabolism , Enhancer of Zeste Homolog 2 Protein , Female , Gene Expression Regulation, Neoplastic , Humans , Kidney Neoplasms/mortality , Male , MicroRNAs/genetics , Middle Aged , Polycomb Repressive Complex 2 , RNA Interference , Transcription Factors/metabolism , Tumor Cells, Cultured
6.
Prostate ; 71(1): 18-25, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-20583131

ABSTRACT

BACKGROUND: Stem cells were suggested to be present in human prostate cancer as a small population of distinct cells, which may contribute to carcinogenesis, tumor recurrence, and chemoresistance. To identify potential prostatic stem cells, we analyzed the expression of several potential stem cell markers in benign prostate and prostatic adenocarcinoma. METHODS: CD44, CD133, Oct4, SOX2, and EZH2 expression was detected by immunohistochemical (IHC) staining using tissue microarray assays (TMA) composed of benign (non-neoplastic) prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and prostatic adenocarcinoma. Positive staining was defined as 1+ (<10%), 2+ (10-50%), or 3+ (>50%). RESULTS: We found CD44 staining in 97% and 72% of benign + HGPIN and malignant lesions, respectively. CD133 staining was detected in a small fraction (4 of 67) of prostate carcinomas. We found that Oct4 nuclear expression was strongly associated with benign lesions and HGPIN but not prostate cancer (P < 0.05). In most cases, nuclear expression of EZH2 and SOX2 was detected in less than 10% of cells in non-neoplastic prostate glands, HGPINs or prostate adenocarcinomas. Moreover, 27 of 33 SOX2 1+ prostate cancers were also EZH2 1+, whereas all 33 of these cases were CD44+. CONCLUSIONS: Expression of CD44 and Oct4 identified large populations of benign and malignant cells in the prostate, which did not fit the definition of stem cells as a small fraction of the total cell population. Our results suggest that combined expression of embryonic stem cell markers EZH2 and SOX2 might identify potential cancer stem cells as a minor (<10%) subgroup in CD44+ prostatic adenocarcinoma.


Subject(s)
Adenocarcinoma/metabolism , Biomarkers, Tumor/metabolism , Neoplastic Stem Cells/metabolism , Prostate/metabolism , Prostatic Intraepithelial Neoplasia/metabolism , Prostatic Neoplasms/metabolism , AC133 Antigen , Adenocarcinoma/pathology , Antigens, CD/analysis , Antigens, CD/metabolism , Biomarkers, Tumor/analysis , DNA-Binding Proteins/analysis , DNA-Binding Proteins/metabolism , Enhancer of Zeste Homolog 2 Protein , Glycoproteins/analysis , Glycoproteins/metabolism , Humans , Hyaluronan Receptors/analysis , Hyaluronan Receptors/metabolism , Male , Neoplastic Stem Cells/pathology , Octamer Transcription Factor-3/analysis , Octamer Transcription Factor-3/metabolism , Peptides/analysis , Peptides/metabolism , Polycomb Repressive Complex 2 , Prostate/pathology , Prostatic Intraepithelial Neoplasia/pathology , Prostatic Neoplasms/pathology , SOXB1 Transcription Factors/analysis , SOXB1 Transcription Factors/metabolism , Transcription Factors/analysis , Transcription Factors/metabolism
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