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1.
Eur J Med Chem ; 213: 113215, 2021 Mar 05.
Article in English | MEDLINE | ID: mdl-33516985

ABSTRACT

Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) is one of the most pursued targets in the treatment of acute myeloid leukaemia (AML) as its gene amplification and mutations, particularly internal tandem duplication (ITD), contribute to the pathogenesis of AML and the resistance to known FLT3 inhibitors. To conquer this challenge, there is a quest for structurally novel FLT3 inhibitors. Herein, we report the discovery of a new series of 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors. Compounds 12b and 12r were capable of suppressing a wide range of mutated FLT3 kinases including ITD and D835Y mutants; the latter isoform is closely associated with acquired drug resistance. In addition, both compounds displayed an anti-proliferative specificity for FLT3-ITD-harbouring cell lines (i.e., MV4-11 and MOLM-13 cells) over those with expression of the wild-type kinase or even without FLT3 expression. In mechanistic studies using MV4-11 cells, 12b was found to diminish the phosphorylation of key downstream effectors of FLT3 and induce apoptosis, supporting an FLT3-ITD-targeted mechanism of its anti-proliferative action.


Subject(s)
Amines/pharmacology , Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Amines/chemical synthesis , Amines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Discovery , Drug Screening Assays, Antitumor , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured , fms-Like Tyrosine Kinase 3/metabolism
2.
BMC Cancer ; 17(1): 820, 2017 Dec 05.
Article in English | MEDLINE | ID: mdl-29207959

ABSTRACT

BACKGROUND: Targeting the type 1 insulin-like growth factor receptor (IGF1R) in breast cancer remains an ongoing clinical challenge. Oncogenic IGF1R-signaling occurs via activation of PI3K/AKT/MAPK downstream mediators which regulate cell proliferation and protein synthesis. To further understand IGF1R signaling we have investigated the involvement of the oncogenic IGF1R-related sphingosine kinase (SphK) pathway. METHODS: The prognostic (overall survival, OS) and therapeutic (anti-endocrine therapy) co-contribution of IGF1R and SphK1 were investigated using breast cancer patient samples (n = 236) for immunohistochemistry to measure total and phosphorylated IGF1R and SphK1. Kaplan-Meier and correlation analyses were performed to determine the contribution of high versus low IGF1R and/or SphK1 expression to OS in patients treated with anti-endocrine therapy. Cell viability and colony formation in vitro studies were completed using estrogen receptor (ER) positive and negative breast cancer cell-lines to determine the benefit of IGF1R inhibitor (OSI-906) and SphK inhibitor (SKI-II) co-therapy. Repeated measures and 1-way ANOVA were performed to compare drug treatments groups and the Chou-Talalay combination index (CI) was calculated to estimate drug synergism in vitro (CI < 1). RESULTS: High IGF1R and SphK1 protein co-expression in tumor tissue was associated with improved OS specifically in ER-positive disease and stratified for anti-endocrine therapy. A significant synergistic inhibition of cell viability and/or colony formation following OSI-906 and SKI-II co-treatment in vitro was evident (p < 0.05, CI < 1). CONCLUSION: We conclude that high IGF1R and SphK1 co-expression act together as prognostic indicators and are potentially, dual therapeutic targets for the development of a more effective IGF1R-directed combination breast cancer therapy.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms, Male/metabolism , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Receptors, Somatomedin/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms, Male/diagnosis , Breast Neoplasms, Male/drug therapy , Breast Neoplasms, Male/mortality , Carcinoma, Ductal, Breast/diagnosis , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/mortality , Cell Survival/drug effects , Drug Synergism , Female , Humans , Kaplan-Meier Estimate , MCF-7 Cells , Male , Middle Aged , Multivariate Analysis , Prognosis , Proportional Hazards Models , Receptor, IGF Type 1 , Treatment Outcome , Young Adult
3.
Endocr Relat Cancer ; 23(11): R513-R536, 2016 11.
Article in English | MEDLINE | ID: mdl-27733416

ABSTRACT

Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers.


Subject(s)
Breast Neoplasms/therapy , Molecular Targeted Therapy/methods , Receptors, Somatomedin/antagonists & inhibitors , Animals , Breast Neoplasms/genetics , Combined Modality Therapy , Drug Resistance, Neoplasm/genetics , Drug Therapy, Combination , Female , Humans , Precision Medicine/methods , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/metabolism , Signal Transduction/genetics
4.
Neoplasia ; 18(2): 100-10, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26936396

ABSTRACT

BACKGROUND: Control of mRNA translation is fundamentally altered in cancer. Insulin-like growth factor-I (IGF-I) signaling regulates key translation mediators to modulate protein synthesis (e.g. eIF4E, 4E-BP1, mTOR, and S6K1). Importantly the Amplified in Breast Cancer (AIB1) oncogene regulates transcription and is also a downstream mediator of IGF-I signaling. MATERIALS AND METHODS: To determine if AIB1 also affects mRNA translation, we conducted gain and loss of AIB1 function experiments in estrogen receptor alpha (ERα)(+) (MCF-7L) and ERα(-) (MDA-MB-231, MDA-MB-435 and LCC6) breast cancer cells. RESULTS: AIB1 positively regulated IGF-I-induced mRNA translation in both ERα(+) and ERα(-) cells. Formation of the eIF4E-4E-BP1 translational complex was altered in the AIB1 ERα(+) and ERα(-) knockdown cells, leading to a reduction in the eIF4E/4E-BP1 and eIF4G/4E-BP1 ratios. In basal and IGF-I stimulated MCF-7 and LCC6 cells, knockdown of AIB1 decreased the integrity of the cap-binding complex, reduced global IGF-I stimulated polyribosomal mRNA recruitment with a concomitant decrease in ten of the thirteen genes tested in polysome-bound mRNAs mapping to proliferation, cell cycle, survival, transcription, translation and ribosome biogenesis ontologies. Specifically, knockdown of AIB1 decreased ribosome-bound mRNA and steady-state protein levels of the transcription factors ERα and E2F1 in addition to reduced ribosome-bound mRNA of the ribosome biogenesis factor BYSL in a cell-line specific manner to regulate mRNA translation. CONCLUSION: The oncogenic transcription factor AIB1 has a novel role in the regulation of polyribosome recruitment and formation of the translational complex. Combinatorial therapies targeting IGF signaling and mRNA translation in AIB1 expressing breast cancers may have clinical benefit and warrants further investigation.


Subject(s)
Breast Neoplasms/genetics , Insulin-Like Growth Factor I/genetics , Nuclear Receptor Coactivator 3/genetics , Protein Biosynthesis , Adaptor Proteins, Signal Transducing/biosynthesis , Breast Neoplasms/pathology , Cell Cycle Proteins , Estrogen Receptor alpha/genetics , Eukaryotic Initiation Factor-4E/biosynthesis , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Insulin-Like Growth Factor I/biosynthesis , MCF-7 Cells , Phosphoproteins/biosynthesis , Phosphorylation , Ribosomal Protein S6 Kinases, 70-kDa/biosynthesis , Signal Transduction/genetics , TOR Serine-Threonine Kinases/biosynthesis
5.
Menopause ; 21(1): 79-88, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23715406

ABSTRACT

OBJECTIVE: Medroxyprogesterone acetate (MPA), a component of combined estrogen-progestin therapy (EPT), has been associated with increased breast cancer risk in EPT users. MPA can bind to the androgen receptor (AR), and AR signaling inhibits cell growth in breast tissues. Therefore, the aim of this study was to investigate the potential of MPA to disrupt AR signaling in an ex vivo culture model of normal human breast tissue. METHODS: Histologically normal breast tissues from women undergoing breast surgical operation were cultured in the presence or in the absence of the native AR ligand 5α-dihydrotestosterone (DHT), MPA, or the AR antagonist bicalutamide. Ki67, bromodeoxyuridine, B-cell CLL/lymphoma 2 (BCL2), AR, estrogen receptor α, and progesterone receptor were detected by immunohistochemistry. RESULTS: DHT inhibited the proliferation of breast epithelial cells in an AR-dependent manner within tissues from postmenopausal women, and MPA significantly antagonized this androgenic effect. These hormonal responses were not commonly observed in cultured tissues from premenopausal women. In tissues from postmenopausal women, DHT either induced or repressed BCL2 expression, and the antiandrogenic effect of MPA on BCL2 was variable. MPA significantly opposed the positive effect of DHT on AR stabilization, but these hormones had no significant effect on estrogen receptor α or progesterone receptor levels. CONCLUSIONS: In a subset of postmenopausal women, MPA exerts an antiandrogenic effect on breast epithelial cells that is associated with increased proliferation and destabilization of AR protein. This activity may contribute mechanistically to the increased risk of breast cancer in women taking MPA-containing EPT.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Breast/drug effects , Epithelial Cells/drug effects , Medroxyprogesterone Acetate/pharmacology , Androgen Antagonists/pharmacology , Androgens/pharmacology , Anilides/pharmacology , Breast/anatomy & histology , Breast/cytology , Bromodeoxyuridine/metabolism , Cell Proliferation/drug effects , Dihydrotestosterone/pharmacology , Epithelial Cells/physiology , Estrogen Receptor alpha/metabolism , Female , Humans , Ki-67 Antigen/metabolism , Nitriles/pharmacology , Postmenopause , Premenopause/physiology , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, Androgen/metabolism , Receptors, Progesterone/metabolism , Signal Transduction/drug effects , Tissue Culture Techniques , Tosyl Compounds/pharmacology
6.
Mol Cell Endocrinol ; 382(2): 899-908, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24239616

ABSTRACT

Medroxyprogesterone acetate (MPA) has widely been used in hormone replacement therapy (HRT), and is associated with an increased risk of breast cancer, possibly due to disruption of androgen receptor (AR) signaling. In contrast, the synthetic HRT Tibolone does not increase breast density, and is rapidly metabolized to estrogenic 3α-OH-tibolone and 3ß-OH-tibolone, and a delta-4 isomer (Δ(4)-TIB) that has both androgenic and progestagenic properties. Here, we show that 5α-dihydrotestosterone (DHT) and Δ(4)-TIB, but not MPA, stabilize AR protein levels, initiate specific AR intramolecular interactions critical for AR transcriptional regulation, and increase proliferation of AR positive MDA-MB-453 breast cancer cells. Structural modeling and molecular dynamic simulation indicate that Δ(4)-TIB induces a more stable AR structure than does DHT, and MPA a less stable one. Microarray expression analyses confirms that the molecular actions of Δ(4)-TIB more closely resembles DHT in breast cancer cells than either ligand does to MPA.


Subject(s)
Androgens/pharmacology , Dihydrotestosterone/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Neoplasm Proteins/genetics , Norpregnenes/pharmacology , Receptors, Androgen/genetics , Androgens/chemistry , Androgens/metabolism , Biotransformation , Cell Line, Tumor , Dihydrotestosterone/chemistry , Dihydrotestosterone/metabolism , Female , Gene Expression Profiling , Humans , Medroxyprogesterone Acetate/chemistry , Medroxyprogesterone Acetate/pharmacology , Molecular Dynamics Simulation , Neoplasm Proteins/metabolism , Norpregnanes/metabolism , Norpregnenes/chemistry , Norpregnenes/metabolism , Oligonucleotide Array Sequence Analysis , Receptors, Androgen/metabolism , Structure-Activity Relationship
7.
Prostate ; 73(2): 182-93, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22782870

ABSTRACT

BACKGROUND: Krüppel-like factor (KLF) 6 is a candidate tumor suppressor gene in prostate cancer, but the mechanisms contributing to its loss of expression are poorly understood. We characterized KLF6 expression and DNA methylation status during prostate tumorigenesis in humans and mice. METHODS: KLF6 expression was assessed in matched human non-malignant (NM) and tumor prostate tissues (n = 22) by quantitative real-time PCR (qPCR) and in three independent human prostate cancer cohorts bioinformatically. QPCR for KLF6 expression and methylation-sensitive PCR (MSP) were performed in human prostate LNCaP cancer cells after 5-aza-2'-deoxycytidine treatment. Klf6 protein levels and DNA promoter methylation were assessed in TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors by immunohistochemistry and MSP, respectively. RESULTS: KLF6 splice variants expression was increased (P = 0.0015) in human prostate tumors compared to NM tissues. Overall, KLF6 was decreased in metastatic compared to primary prostate cancers and reduced expression in primary tumors was associated with a shorter time to relapse (P = 0.0028). Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in up-regulation of KLF6 expression (two-fold; P = 0.002) and a decrease in DNA methylation of the KLF6 promoter in LNCaP cells. Klf6 protein levels significantly decreased with progression in the TRAMP model of prostate cancer (P < 0.05), but there was no difference in Klf6 promoter methylation. CONCLUSION: KLF6 expression was decreased in both clinical prostate cancer and the TRAMP model with disease progression, but this could not be explained by DNA methylation of the KLF6 promoter.


Subject(s)
Disease Progression , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Kruppel-Like Transcription Factors/antagonists & inhibitors , Kruppel-Like Transcription Factors/genetics , Prostatic Neoplasms/genetics , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , Animals , Cell Line, Tumor , Cohort Studies , Down-Regulation/genetics , Humans , Kruppel-Like Factor 6 , Kruppel-Like Transcription Factors/biosynthesis , Male , Mice , Mice, Transgenic , Prostatic Neoplasms/etiology , Prostatic Neoplasms/metabolism , Proto-Oncogene Proteins/biosynthesis , Tumor Cells, Cultured , Xenograft Model Antitumor Assays/methods
8.
Breast Cancer Res ; 14(3): 309, 2012 May 10.
Article in English | MEDLINE | ID: mdl-22574877

ABSTRACT

Identification of molecules and their effectors has led to new therapies designed to specifically inhibit pathways in molecularly defined breast cancer subtypes. An orphan nuclear receptor, estrogen-related receptor alpha, has been shown to be a downstream target of two tyrosine kinase growth factor receptors: human epidermal growth factor receptor 2 and the type I insulin-like growth factor receptor. Identifying the mechanistic actions of orphan nuclear receptors could lead to new biomarkers and molecular targets in malignancy.


Subject(s)
Breast Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Receptor, IGF Type 1/metabolism , Receptors, Estrogen/metabolism , Breast Neoplasms/therapy , Carrier Proteins/metabolism , Cell Line , Female , Heat-Shock Proteins/metabolism , Humans , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , RNA-Binding Proteins , Signal Transduction , Transcription Factors/metabolism , ERRalpha Estrogen-Related Receptor
9.
Int J Cancer ; 131(3): 652-61, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22052531

ABSTRACT

Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. The objective of this study was to use a mouse model of prostate cancer as a tool to discover serum miRNAs that could be assessed in a clinical setting. Global miRNA profiling identified 46 miRNAs at significantly altered levels (p ≤ 0.05) in the serum of TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice with advanced prostate cancer compared to healthy controls. A subset of these miRNAs with known human homologues were validated in an independent cohort of mice and then measured in serum from men with metastatic castration-resistant prostate cancer (mCRPC; n = 25) or healthy men (n = 25). Four miRNAs altered in mice, mmu-miR-141, mmu-miR-298, mmu-miR-346 and mmu-miR-375, were also found to be at differential levels in the serum of men with mCRPC. Three of these (hsa-miR-141, hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue, suggesting that they are released into the blood as disease progresses. Moreover, the intra-tumoral expression of hsa-miR-141 and hsa-miR-375 were predictors of biochemical relapse after surgery. This study is the first to demonstrate that specific serum miRNAs are common between human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the discovery of novel biomarkers.


Subject(s)
Biomarkers, Tumor/blood , MicroRNAs/blood , Prostatic Neoplasms/genetics , Animals , Biomarkers, Tumor/genetics , Gene Expression Profiling , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , MicroRNAs/genetics , Oligonucleotide Array Sequence Analysis , Prognosis , Prostatic Neoplasms/blood , Prostatic Neoplasms/pathology
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