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1.
Prostate ; 79(15): 1777-1788, 2019 11.
Article in English | MEDLINE | ID: mdl-31503357

ABSTRACT

BACKGROUND: Gleason grade is among the most powerful clinicopathological classification systems used to assess risk of lethal potential in prostate cancer, yet its biologic basis is poorly understood. Notably, pure low-grade cancers, comprised predominantly of Gleason pattern 3 (G3) are typically indolent, with lethal potential emerging with the progression of higher-grade Gleason patterns 4 (G4) or 5. One of the hallmarks of more aggressive cancer phenotypes is the stereotyped set of metabolic characteristics that transformed cells acquire to facilitate unregulated growth. In the present study, we profiled expression signatures of metabolic genes that are differentially expressed between G3 and G4 cancer foci and investigated the functional role of two of the profiled genes, PGRMC1 and HSD17B4, in prostate cancer cells. METHODS: Gene expression profiling was conducted using 32 G3 and 32 G4 cancer foci from patients with 3+3 and ≥4+3 tumors, respectively. A 95-gene Nanostring probe set was used to probe genes associated with energy metabolism. Two out of five genes (PGRMC1 and HSD17B4) that significantly distinguish between G3 and G4 were functionally validated in vitro using established prostate cancer cells (PC3, DU145). Expression of PGRMC1 and HSD17B4 was knocked down and subsequent studies were performed to analyze cell proliferation, migration, invasion, and apoptosis. Mechanistic studies that explored the epidermal growth factor receptor (EGFR) pathway were performed by Western blot. RESULTS: Multivariate analysis identified five metabolic genes that were differentially expressed between G3 and G4 stroma (P < .05). Functional validation studies revealed that knockdown of PGRMC1 and HSD17B4 significantly decreased cell proliferation, migration, and invasion, and increased apoptosis in PC3 and DU145 cells. Mechanistic studies showed that these effects, after PGRMC1 knockdown, were possibly mediated through alterations in downstream components of the EGFR, protein kinase B, and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. CONCLUSION: The following study provides evidence supporting the use of metabolic genes PGRMC1 and HSD17B4 as a prognostic biomarker for the distinction between G3 and G4 prostate cancers.


Subject(s)
Gene Expression Regulation, Neoplastic , Prostate/pathology , Prostatic Neoplasms/genetics , Cell Line, Tumor , Disease Progression , Gene Expression Profiling , Humans , Male , Neoplasm Grading , Prostatic Neoplasms/pathology
2.
Prostate ; 79(2): 151-159, 2019 02.
Article in English | MEDLINE | ID: mdl-30242861

ABSTRACT

BACKGROUND: Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer. In the present study, we explored the anti-cancer effects of the synthetic cannabinoid WIN 55,212-2 (WIN) in prostate cancer. METHODS: Established prostate cancer cells (PC3, DU145, LNCaP) were treated with varying concentrations of WIN. Cell proliferation was determined by the MTS assay. The anti-migration and anti-invasive potential of WIN was examined by the wound healing assay and the matrigel invasion assay. Cell cycle analysis was performed by flow cytometry, and mechanistic studies were performed by Western blot. Athymic mice (n = 10) were inoculated with human PC3 cells. Once tumors reached 100 mm3 , animals were randomized into two groups: saline control and WIN (5 mg/kg), delivered by intraperitoneal injection three times per week for 3 weeks. RESULTS: WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose-dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre-treatment with a CB2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti-proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control (P < 0.05). CONCLUSIONS: The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer.


Subject(s)
Benzoxazines/pharmacology , Morpholines/pharmacology , Naphthalenes/pharmacology , Prostatic Neoplasms/drug therapy , Receptor, Cannabinoid, CB2/metabolism , Animals , Apoptosis/drug effects , Cannabinoid Receptor Antagonists/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Interactions , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Indoles/pharmacology , Male , Mice , Mice, Nude , Neoplasm Invasiveness , PC-3 Cells , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Random Allocation , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Resting Phase, Cell Cycle/drug effects , Xenograft Model Antitumor Assays
3.
Anticancer Res ; 39(1): 113-118, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30591447

ABSTRACT

BACKGROUND/AIM: Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. It has recently been demonstrated to inhibit tumor progression and metastasis in breast cancer models. Docetaxel is a chemotherapy agent for castrate-resistant prostate cancer (CRPC). In this study, the ability of CRPC cells to grow and develop in vivo tumors in an animal model was evaluated, in order to investigate the anti-tumor effect of desmopressin in combination with docetaxel. MATERIALS AND METHODS: The CRPC cell line PC3 was used for orthotopic inoculation in male athymic nude mice. The mice were randomly assigned to one of the four treatment groups: Control, docetaxel, desmopressin or combination therapy. Following the last treatment, tumors were excised and measured. Blood samples were processed for CTC analysis. RESULTS: Docetaxel treatment resulted in a significant reduction in tumor volume compared to control. The combination therapy resulted in even more significant reduction (31.2%) in tumor volume. There was a complete absence of CTCs in the combination group. CONCLUSION: Our pilot study demonstrated an enhanced efficacy of docetaxel-based therapy in combination with desmopressin.


Subject(s)
Deamino Arginine Vasopressin/administration & dosage , Docetaxel/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Male , Mice , Pilot Projects , Prostatic Neoplasms, Castration-Resistant/pathology , Tumor Burden , Xenograft Model Antitumor Assays
4.
Prostate Cancer Prostatic Dis ; 21(2): 187-195, 2018 06.
Article in English | MEDLINE | ID: mdl-29242596

ABSTRACT

BACKGROUND: Research examining the association between physical activity (PA) and prostate cancer (PCa) has accumulated; however, few studies have examined this association in the context of active surveillance. The current study examines this among men initially diagnosed with favorable-risk PCa and managed by active surveillance at Sunnybrook Health Sciences Centre in Canada and the Royal Marsden Hospital in the United Kingdom. METHODS: Participants completed a questionnaire on daily participation in non-leisure, transport, and recreational PA. A logistic regression was employed using PA as the independent variable and whether the patient reclassified to higher-risk PCa while on active surveillance as the dependent variable. Demographic and lifestyle covariates were incorporated in the analysis to assess potential confounding and effect modification. RESULTS: Men from both hospitals presented with similar clinical and demographic characteristics. Total PA was inversely associated with odds of reclassification while on active surveillance (p-trend = 0.027). A weaker inverse association was observed with recreational PA (p-trend = 0.30). Men who participated in weekly vigorous PA were less likely to reclassify than those who did not (odds ratio (95% confidence interval): 0.42 (0.20-0.85)). CONCLUSIONS: Total and vigorous PA were inversely associated with odds of reclassification in two active surveillance cohorts. Given the limitations of this study, more robust prospective observational studies involving objective PA measures are warranted to confirm findings.


Subject(s)
Energy Metabolism , Exercise , Life Style , Population Surveillance , Prostatic Neoplasms/classification , Aged , Cohort Studies , Disease Progression , Follow-Up Studies , Humans , Male , Middle Aged , Motor Activity , Prognosis , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/pathology , Risk Factors , Surveys and Questionnaires , Time Factors
5.
Anticancer Res ; 37(12): 6601-6607, 2017 12.
Article in English | MEDLINE | ID: mdl-29187435

ABSTRACT

BACKGROUND/AIM: Docetaxel, the first-line chemotherapy for metastatic castration-resistant prostate cancer (mCRPC), provides certain survival benefits, but is associated with significant toxicity. A novel therapeutic approach for mCRPC is combining docetaxel with a chemosensitizing agent. We hypothesized that metformin, a potential chemosensitizer, would improve docetaxel efficacy in CRPC cells. MATERIALS AND METHODS: MTS assays were used to determine the effect of metformin-docetaxel treatment on PC3 and DU145 cell viability. Wound-healing and ATP concentration assays were used to evaluate cell migration and intracellular ATP levels following metformin-docetaxel treatment. Western blotting was used for mechanistic evaluation. RESULTS: Metformin-docetaxel treatment significantly reduced PC3 cell viability. Metformin-docetaxel treatment did not significantly affect cell migration or intracellular ATP levels. Western blotting revealed metformin-docetaxel treatment did not significantly change AMPK or P-AMPK expression patterns. CONCLUSION: Metformin may be an effective chemosensitizer for certain types of CRPC cells, but further investigation is needed.


Subject(s)
Cell Movement/drug effects , Metformin/pharmacology , Taxoids/pharmacology , AMP-Activated Protein Kinases/metabolism , Adenosine Triphosphate/metabolism , Blotting, Western , Cell Line, Tumor , Cell Survival/drug effects , Docetaxel , Drug Screening Assays, Antitumor , Drug Synergism , Humans , Male , Phosphorylation/drug effects , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology
6.
J Urol ; 197(4): 1068-1075, 2017 04.
Article in English | MEDLINE | ID: mdl-27984108

ABSTRACT

PURPOSE: Docetaxel is the first line chemotherapy currently used to treat patients with symptomatic metastatic castration resistant prostate cancer. Although it provides survival benefits, it is associated with significant side effects. Novel therapeutic options are needed for patients with metastatic castration resistant prostate cancer and an approach is combining docetaxel with chemosensitizing agents. Metformin has been shown to improve the survival of patients with breast, lung and endometrial cancer receiving chemotherapy, and enhance chemotherapeutic efficacy in breast cancer and colon cancer cells. However, to our knowledge the chemosensitizing effect of metformin in prostate cancer has not been explored. Therefore, the hypothesis for our study was that diabetic patients with metastatic castration resistant prostate cancer who were administered metformin during docetaxel chemotherapy would have improved prostate cancer specific and overall survival. MATERIALS AND METHODS: This retrospective cohort study used data from several Ontario administrative health care databases. Men older than 65 years diagnosed with metastatic castration resistant prostate cancer and treated with docetaxel were stratified into groups based on diabetes status and use of antidiabetic medications. We evaluated the effect of metformin use with docetaxel on prostate cancer specific survival and overall survival using Kaplan-Meier survival curves, the log rank test and multivariate Cox proportional HRs. RESULTS: Survival curves showed that metformin use with docetaxel did not improve prostate cancer specific survival (p = 0.9562) or overall survival (p = 0.9927). HRs showed no significant effect of metformin use with docetaxel on prostate cancer specific survival (HR = 0.96, p = 0.66) or overall survival (HR = 0.94, p = 0.39). CONCLUSIONS: Metformin use during docetaxel chemotherapy did not significantly improve prostate cancer specific or overall survival in diabetic patients with metastatic castration resistant prostate cancer. This study indicates that metformin may not be an effective chemosensitizer for metastatic castration resistant prostate cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Diabetes Complications/drug therapy , Diabetes Complications/mortality , Diabetes Mellitus/drug therapy , Docetaxel/therapeutic use , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/mortality , Aged , Aged, 80 and over , Cohort Studies , Drug Therapy, Combination , Humans , Male , Middle Aged , Retrospective Studies , Survival Rate
7.
J Urol ; 197(2): 335-341, 2017 02.
Article in English | MEDLINE | ID: mdl-27545574

ABSTRACT

PURPOSE: Patients with prostate cancer on active surveillance are monitored by repeat prostate specific antigen measurements, digital rectal examinations and prostate biopsies. A subset of patients on active surveillance will later reclassify with disease progression, prompting definitive treatment. To minimize the risk of under treating such patients on active surveillance minimally invasive tests are urgently needed incorporating biomarkers to identify patients who will reclassify. MATERIALS AND METHODS: We assessed post-digital rectal examination urine samples of patients on active surveillance for select DNA methylation biomarkers that were previously investigated in radical prostatectomy specimens and shown to correlate with an increasing risk of prostate cancer. Post-digital rectal examination urine samples were prospectively collected from 153 men on active surveillance who were diagnosed with Gleason score 6 disease. Urinary sediment DNA was analyzed for 8 DNA methylation biomarkers by multiplex MethyLight assay. Correlative analyses were performed on gene methylation and clinicopathological variables to test the ability to predict patient risk reclassification. RESULTS: Using backward logistic regression a 4-gene methylation classifier panel (APC, CRIP3, GSTP1 and HOXD8) was identified. The classifier panel was able to predict patient reclassification (OR 2.559, 95% CI 1.257-5.212). We observed this panel to be an independent and superior predictor compared to current clinical predictors such as prostate specific antigen at diagnosis or the percent of tumor positive cores in the initial biopsy. CONCLUSION: We report that a urine based classifier panel of 4 methylation biomarkers predicts disease progression in patients on active surveillance. Once validated in independent active surveillance cohorts, these promising biomarkers may help establish a less invasive method to monitor patients on active surveillance programs.


Subject(s)
Biomarkers, Tumor/urine , DNA Methylation/genetics , Prostatic Neoplasms/urine , Adult , Aged , Aged, 80 and over , Digital Rectal Examination , Disease Progression , Humans , Male , Middle Aged , Multiplex Polymerase Chain Reaction/methods , Neoplasm Grading , Predictive Value of Tests , Prospective Studies , Prostate/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Risk Assessment/methods
8.
Biochem Biophys Res Commun ; 464(3): 848-54, 2015 Aug 28.
Article in English | MEDLINE | ID: mdl-26182875

ABSTRACT

BACKGROUND: This study was designed to assess the effectiveness of a combination treatment using both desmopressin and docetaxel in prostate cancer treatment. Desmopressin is a well-known synthetic analogue of the antidiuretic hormone vasopressin. It has recently been demonstrated to inhibit tumor progression and metastasis in in vivo models. Docetaxel is widely used for the treatment of castration resistant prostate cancer (CRPC) patients. However, durable responses have been uncommon to date. In this study, we investigated the anti-tumor effect of desmopressin in combination with docetaxel in vitro and in vivo. METHODS: Two prostate cancer cells (PC3, LNCaP) were treated with different concentrations of desmopressin alone, docetaxel alone, and a combination of desmopressin and docetaxel. Cell proliferation was determined by MTS assay. The anti-invasive and anti-migration potential of desmopressin and in combination with docetaxel were examined by wound healing assay, migration chamber assay, and matrigel invasion assay. RESULTS: The combination of desmopressin and docetaxel resulted in a significant inhibition of PC3 and LNCaP cell proliferation (p < 0.01). Additionally, cell migration and invasion were also inhibited by the combination when compared to that of either treatment alone in PC3 cells (p < 0.01). The anti-tumor effect of this combination treatment was associated with down-regulation of both urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP-2 and MMP-9) in PC3 cells. CONCLUSIONS: We are the first to elucidate the anti-tumor and anti-metastatic potential of desmopressin in combination with docetaxel in a prostate cancer model via the uPA-MMP pathway. Our finding could potentially contribute to the therapeutic profile of desmopressin and enhance the efficacy of docetaxel based treatment for CRPC.


Subject(s)
Deamino Arginine Vasopressin/pharmacology , Prostatic Neoplasms/drug therapy , Taxoids/pharmacology , Urokinase-Type Plasminogen Activator/metabolism , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Deamino Arginine Vasopressin/administration & dosage , Docetaxel , Dose-Response Relationship, Drug , Humans , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice, Nude , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Taxoids/administration & dosage , Xenograft Model Antitumor Assays
9.
Prostate ; 75(12): 1300-11, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26047020

ABSTRACT

BACKGROUND: Capsaicin, the active compound in chili peppers, has demonstrated anti- carcinogenic properties in vitro in a number of malignancies, including the prostate. In the present study, we investigate the chemopreventive potential of capsaicin on prostate cancer using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The TRAMP is a murine model that resembles the progression of human disease. METHODS: Thirty-five 6-week-old TRAMP x C57BL/6 mice were randomized between treatment with capsaicin (5 mg/kg body weight) or control (saline) three times a week by oral gavage until 30 weeks of age. Body weight of animals was recorded thrice weekly. At termination, all tumors were extracted, recorded, and analyzed for histopathological analysis. To understand the effect of capsaicin on migration and invasion, in vitro experiments were carried out using PC3 cells. RESULTS: Mice in the control group expressed an overall trend of higher-grade disease with 37.5% poorly differentiated (PD), 18.75% moderately differentiated (MD), and 44% of well-differentiated (WD) adenocarcinoma, compared to the capsaicin-treated group with only 27.7% PD, 61.0% of WD, and 11.1% of intraepithelial neoplasia (PIN). The treatment group demonstrated a higher incidence of noncancerous PIN lesions compared to the control group. The capsaicin group also demonstrated a significant reduction (P < 0.05) in the metastatic burden compared to the controls, which correlated to a reduction in p27(Kip) (1) expression and neuroendocrine differentiation in prostate tumors. Furthermore, there were no differences in body weight between groups overtime, and no pathological toxicities in the liver and gastrointestinal tract with capsaicin consumption. In vitro studies revealed a dose-dependent reduction in the invasion and migration capacity of PC3 cells. CONCLUSION: The following study provides evidence supporting the safety and chemopreventive effects of capsaicin in the TRAMP model.


Subject(s)
Adenocarcinoma/drug therapy , Anticarcinogenic Agents/pharmacology , Capsaicin/pharmacology , Prostatic Neoplasms/drug therapy , Sensory System Agents/pharmacology , Adenocarcinoma/pathology , Administration, Oral , Animals , Cell Line, Tumor , Chromatography, Liquid , Disease Models, Animal , Disease Progression , Humans , Immunohistochemistry , Male , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mice, Transgenic , Prostatic Neoplasms/pathology , Wound Healing
10.
Lipid Insights ; 8: 11-9, 2015.
Article in English | MEDLINE | ID: mdl-25987846

ABSTRACT

We examined whether serum from obese, compared to non-obese, PCa (prostate cancer) patients creates a growth-enhancing tumor micro-environment in vitro. Serum from 80 subjects was divided into four groups: normal weight men with and without PCa and overweight/obese men with and without PCa. Cell proliferation, migration, and invasion were measured in LNCaP, and PC3 cells treated with patient serum were obtained from the above groups. The results reveal that proliferation of LNCaP cells was significantly (P = 0.05) greater with serum from non-obese (mean = 1.26 ± 0.20) compared to that from obese patients (mean = 1.16 ± 0.19). Serum from obese PCa patients compared to non-obese PCa patients induced significantly greater amounts of cell migration (P < 0.01) in PC3 cells. Serum from obese patients induced significantly (P < 0.01) lower amounts of cell invasion (mean = 8.2 ± 4.5) compared to non-obese patients (mean = 18.1 ± 5.0) when treated on PC3 cells. Serum TNF-α (tumor necrosis factor alpha) levels correlated with LNCaP cell proliferation in vitro in non-obese PCa (P < 0.01) and non-obese control groups (P = 0.05). All statistical calculations controlled for age, since the PCa patient groups were significantly older than the control groups (P < 0.01). In conclusion, serum from obese PCa patients induced greater PCa cell migration and lower cell proliferation and invasion in vitro.

11.
Semin Cancer Biol ; 35 Suppl: S199-S223, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25865775

ABSTRACT

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.


Subject(s)
Carcinogenesis/drug effects , Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Tumor Microenvironment/genetics , Antineoplastic Agents/therapeutic use , Carcinogenesis/genetics , Cell Proliferation/drug effects , Humans , Molecular Targeted Therapy , Neoplasms/genetics , Neoplasms/prevention & control , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/prevention & control , Signal Transduction , Tumor Microenvironment/drug effects
12.
Prostate ; 75(2): 113-25, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25307418

ABSTRACT

INTRODUCTION: Radio-sensitizing agents sensitize tumor cells to the lethal effects of radiotherapy (RT) allowing for use of lower doses of radiation to achieve equivalent cancer control, while minimizing adverse effects to normal tissues. Given their limited toxicity and ability to easily integrate into the diet, compounds occurring naturally in the diet make ideal potential radio-sensitizing agents. In this study, we have examined whether capsaicin, the active compound in chilli peppers, can modulate the response to RT in preclinical models of prostate cancer (PCa). METHODS: The effects of RT (1-8 Gy) and/or capsaicin (1-10 µM) on colony formation rates in human PCa cells were assessed using clonogenic assays. Mechanistic studies were performed by Western Blot, immunocytochemistry, and flow cytometry. Athymic mice (n = 40) were inoculated with human LNCaP cells. Once tumors reached 100 mm(3) , animals were randomized into four groups: control, capsaicin alone (5 mg/kg/d), RT alone (6 Gy), and capsaicin and RT. RESULTS: Capsaicin reduced colony formation rates and radio-sensitized human PCa cells (Sensitizer enhancement ratio = 1.3) which corresponded to the suppression of NFκB, independent of TRP-V1 receptor. Cell cycle modulation occurred following RT and capsaicin treatment independently. In vivo, oral administration of capsaicin with RT resulted in a 'greater than additive' growth delay and reduction in the tumor growth rate greater than capsaicin (P < 0.001) or RT (P < 0.03) alone. Immunohistochemical analysis revealed a reduction in proliferation and NFκB expression, and increase in DNA damage. DISCUSSION: Our findings suggest that capsaicin acts as a radio-sensitzing agent for PCa through the inhibition of NFκB signalling.


Subject(s)
Capsaicin/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/radiotherapy , Radiation-Sensitizing Agents/therapeutic use , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Nude , Prostatic Neoplasms/pathology , Xenograft Model Antitumor Assays/methods
14.
Prostate ; 73(11): 1223-32, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23630020

ABSTRACT

BACKGROUND: The relationships between diet, exercise, and prostate cancer (PCa) remain unclear. We have previously reported that a "Western" diet promotes PCa tumor growth in vivo. Presently, we report the effects of sustained aerobic exercise on PCa progression in animals fed a high-fat diet versus a standard diet. METHODS: Athymic mice (n = 43) were inoculated subcutaneously with human PCa (LNCaP) cells, fed ad libitum with either a high-fat or a standard diet, and randomized into forced exercising and non-exercising groups. Body weight, tumor volume, and food consumption were recorded tri-weekly. Terminal serum samples and tumor biopsies were obtained for analysis. RESULTS: Body weight differences were not observed between the groups over time. The high-fat diet with exercise (HF-Ex) group showed significantly increased tumor growth rate compared to all other groups (P < 0.0007). Tumor growth rate of the standard diet with exercise (Std-Ex) group was reduced significantly compared to the high-fat diet without exercise (HF-No Ex) group (P = 0.0008). Significant differences (P ≤ 0.012) were observed in energy consumption (kcal) between the groups over time. Exercising mice consumed significantly more kcal than non-exercising mice, and the HF-Ex group consumed significantly more than each of the other three groups (P < 0.0007). The expression levels of p27 and p21 were increased in exercising animals, while AR expression was elevated in the HF-Ex group versus the Std-Ex and HF-No Ex groups. CONCLUSIONS: Sustained aerobic exercise did not counteract the tumor-promotional effect of increased consumption of a high-fat diet, suggesting that diet is more influential in PCa progression than exercise. Combining exercise with a healthy diet reduced the rate of PCa progression in this model. This study may have implications for PCa risk reduction in humans.


Subject(s)
Diet, High-Fat/adverse effects , Physical Conditioning, Animal/physiology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/prevention & control , Animals , Cell Line, Tumor , Contraindications , Diet, High-Fat/methods , Energy Intake/physiology , Humans , Male , Mice , Mice, Nude , Physical Conditioning, Animal/methods , Risk Factors , Xenograft Model Antitumor Assays/methods
15.
Lipid Insights ; 6: 37-45, 2013.
Article in English | MEDLINE | ID: mdl-25278767

ABSTRACT

Obesity has been linked to more aggressive characteristics of several cancers, including breast and prostate cancer. Adipose tissue appears to contribute to paracrine interactions in the tumor microenvironment. In particular, cancer-associated adipocytes interact reciprocally with cancer cells and influence cancer progression. Adipokines secreted from adipocytes likely form a key component of the paracrine signaling in the tumor microenvironment. In vitro coculture models allow for the assessment of specific adipokines in this interaction. Furthermore, micronutrients and macronutrients present in the diet may alter the secretion of adipokines from adipocytes. The effect of dietary fat and specific fatty acids on cancer progression in several in vivo model systems and cancer types is reviewed. The more common approaches of caloric restriction or diet-induced obesity in animal models establish that such dietary changes modulate tumor biology. This review seeks to explore available evidence regarding how diet may modulate tumor characteristics through changes in the role of adipocytes in the tumor microenvironment.

16.
J Urol ; 188(2): 502-6, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22704098

ABSTRACT

PURPOSE: Urinary incontinence can be a significant complication of radical prostatectomy. It can be treated with post-prostatectomy surgical procedures. The long-term rate of patients who undergo these surgeries, including artificial urinary sphincter or urethral sling insertion, is not well described. We examined the long-term rate of post-prostatectomy incontinence surgery and factors influencing it. MATERIALS AND METHODS: We performed a population based study of 25,346 men who underwent radical prostatectomy for prostate cancer in Ontario, Canada between 1993 and 2006. We used hospital and cancer registry administrative data to identify patients from this cohort who were later treated with surgery for urinary incontinence. RESULTS: Of the 25,346 patients 703 (2.8%) underwent artificial urinary sphincter insertion and 282 (1.1%) underwent urethral sling placement a median of 2.9 years after prostatectomy. The probability of an artificial urinary sphincter/sling procedure increased with time from prostatectomy. Cumulative 5, 10 and 15-year Kaplan-Meier rates of an artificial urinary sphincter/sling procedure were 2.6% (95% CI 2.4-2.8), 3.8% (95% CI 3.6-4.1) and 4.8% (95% CI 4.4-5.3), respectively. Factors predicting surgery for incontinence were patient age at radical prostatectomy (HR 1.24 per decade, 95% CI 1.11-1.38, p = 0.0002), radiotherapy after surgery (HR 1.61, 95% CI 1.36-1.90, p <0.0001) and surgeon volume (49 or greater prostatectomies per year) (HR 0.59, 95% CI 0.46-0.77, p <0.0001). CONCLUSIONS: Of patients who undergo radical prostatectomy 5% are expected to be treated with surgery for urinary incontinence during a 15-year period. Increasing patient age, radiation treatment and low surgeon volume are associated with significantly higher risk.


Subject(s)
Postoperative Complications/surgery , Prostatectomy , Prostatic Neoplasms/surgery , Urinary Incontinence/surgery , Adult , Aged , Follow-Up Studies , Health Surveys , Humans , Male , Middle Aged , Ontario , Postoperative Complications/epidemiology , Prospective Studies , Prostatic Neoplasms/epidemiology , Reoperation/statistics & numerical data , Suburethral Slings , Urinary Incontinence/epidemiology , Urinary Sphincter, Artificial
17.
Cancer Biol Ther ; 12(11): 997-1004, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-22130093

ABSTRACT

PURPOSE: To identify and examine polymorphisms of genes associated with aggressive and clinical significant forms of prostate cancer among a screening cohort. EXPERIMENTAL DESIGN: We conducted a genome-wide association study among patients with aggressive forms of prostate cancer and biopsy-proven normal controls ascertained from a prostate cancer screening program. We then examined significant associations of specific polymorphisms among a prostate cancer screened cohort to examine their predictive ability in detecting prostate cancer. RESULTS: We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p value for association 1.3 × 10(-10 ) to 3.2 × 10(-11) ) and 15q21 (rs4775302 and rs1994198, p values for association 3.1 × 10(-8 ) to 8.2 × 10(-9)) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8-3.0, p value 0.003-0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk. CONCLUSIONS: Five SNPs were found to be associated with aggressive forms of prostate cancer. We demonstrated potential clinical applications of these associations.


Subject(s)
Chromosomes, Human, Pair 10 , Chromosomes, Human, Pair 15 , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Alleles , Biopsy , Gene Frequency , Genotype , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , ROC Curve , Risk Factors , Sensitivity and Specificity
18.
Int J Oncol ; 39(4): 907-13, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21769423

ABSTRACT

This study demonstrates the ability to generate antigen-specific cytotoxic T cells (CTLs) against HER2 using a xenoantigenic immune stimulation strategy. Dendritic cells (DCs) were transduced with an adenovirus vector incorporating full-length cDNA for rat (xenoantigen) epidermal growth factor receptor 2 (Adv-HER2). Stimulation of autologous T cells with Adv-HER2 infected DCs led to enhanced HER2-specific reactivity as assessed by quantitative real-time polymerase chain reaction (qRT-PCR) for T cell IFN-γ mRNA. In ELISPOT and intracellular cytokine staining (ICS) assays, CD8+ CTLs induced by Adv-HER2 transduced DCs released IFN-γ following stimulation with irradiated autologous DCs infected with Adv-HER2 or loaded with a human prostate cancer cell line (LNCaP) lysate. DCs pulsed with HER2 peptides were less stimulatory than Adv-HER2 transduced DCs. HER2 DC induced CTL lysed HER2+ HLA-A2+ tumor cells (MCF-7); significantly reduced lysis occurred in HER2+ HLA-A2- tumor cells (SKOV-3), and the NK cell sensitive cell line K-562.


Subject(s)
Dendritic Cells/physiology , Receptor, ErbB-2/immunology , T-Lymphocytes, Cytotoxic/immunology , Adenoviridae/genetics , Adenoviridae/metabolism , Animals , Antibodies/immunology , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Antigens, Neoplasm/metabolism , Cancer Vaccines/genetics , Cancer Vaccines/immunology , Cancer Vaccines/metabolism , Cell Line, Tumor , Cytotoxicity, Immunologic/genetics , Cytotoxicity, Immunologic/immunology , Dendritic Cells/immunology , HLA-A2 Antigen/immunology , Humans , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/genetics , Interferon-gamma/metabolism , K562 Cells , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphocyte Activation , Rats , Receptor, ErbB-2/biosynthesis , Receptor, ErbB-2/genetics , Transduction, Genetic/methods
19.
J Clin Oncol ; 29(22): 2959-64, 2011 Aug 01.
Article in English | MEDLINE | ID: mdl-21690464

ABSTRACT

PURPOSE: Prostate cancer risk calculators incorporate many factors to evaluate an individual's risk for prostate cancer. We validated two common North American-based, prostate cancer risk calculators. PATIENTS AND METHODS: We conducted a prospective, multi-institutional study of 2,130 patients who underwent a prostate biopsy for prostate cancer detection from five centers. We evaluated the performance of the Sunnybrook nomogram-based prostate cancer risk calculator (SRC) and the Prostate Cancer Prevention Trial (PCPT) -based risk calculator (PRC) to predict the presence of any cancer and high-grade cancer. We examined discrimination, calibration, and decision curve analysis techniques to evaluate the prediction models. RESULTS: Of the 2,130 patients, 867 men (40.7%) were found to have cancer, and 1,263 (59.3%) did not have cancer. Of the patients with cancer, 403 (46.5%) had a Gleason score of 7 or more. The area under the [concentration-time] curve (AUC) for the SRC was 0.67 (95% CI, 0.65 to 0.69); the AUC for the PRC was 0.61 (95% CI, 0.59 to 0.64). The AUC was higher for predicting aggressive disease from the SRC (0.72; 95% CI, 0.70 to 0.75) compared with that from the PRC (0.67; 95% CI, 0.64 to 0.70). Decision curve analyses showed that the SRC performed better than the PRC for risk thresholds of more than 30% for any cancer and more than 15% for aggressive cancer. CONCLUSION: The SRC performed better than the PRC, but neither one added clinical benefit for risk thresholds of less than 30%. Further research is needed to improve the AUCs of the risk calculators, particularly for higher-grade cancer.


Subject(s)
Biomarkers, Tumor/blood , Biopsy , Decision Support Techniques , Prostate-Specific Antigen/blood , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/prevention & control , Aged , Area Under Curve , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Nomograms , Predictive Value of Tests , Prospective Studies , Prostatic Neoplasms/blood , ROC Curve , Risk Assessment , Risk Factors , Sensitivity and Specificity
20.
PLoS One ; 5(9): e12601, 2010 Sep 07.
Article in English | MEDLINE | ID: mdl-20830292

ABSTRACT

Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33-34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca(2+) signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis.


Subject(s)
Calcium/metabolism , Drug Resistance, Neoplasm , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Prostatic Neoplasms/genetics , Selenium/pharmacology , Signal Transduction , Apoptosis/drug effects , Cell Line, Tumor , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/physiopathology , Selenium/metabolism
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