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1.  Preclinical Evaluation of the Supercritical Extract of Azadirachta Indica (Neem) Leaves In Vitro and In Vivo on Inhibition of Prostate Cancer Tumor Growth 
Molecular cancer therapeutics  2014;13(5):1067-1077.
Azadirachta indica, commonly known as neem, has gained worldwide prominence because of its medical properties, namely antitumor, antiviral, anti-inflammatory, antihyperglycemic, antifungal, and antibacterial activities. Despite these promising results, gaps remain in our understanding of the molecular mechanism of action of neem compounds and their potential for use in clinical trials. We investigated supercritical extract of neem leaves (SENL) for the following: molecular targets in vitro, in vivo efficacy to inhibit tumor growth, and bioactive compounds that exert antitumor activity. Treatment of LNCaP-luc2 prostate cancer cells with SENL suppressed dihydrotestosterone-induced androgen receptor and prostate-specific antigen levels. SENL inhibited integrin β1, calreticulin, and focal adhesion kinase activation in LNCaP-luc2 and PC3 prostate cancer cells. Oral administration of SENL significantly reduced LNCaP-luc2 xenograft tumor growth in mice with the formation of hyalinized fibrous tumor tissue, reduction in the prostate-specific antigen, and increase in AKR1C2 levels. To identify the active anticancer compounds, we fractionated SENL by high-pressure liquid chromatography and evaluated 16 peaks for cytotoxic activity. Four of the 16 peaks exhibited significant cytotoxic activity against prostate cancer cells. Mass spectrometry of the isolated peaks suggested the compounds with cytotoxic activity were nimbandiol, nimbolide, 2′,3′-dihydronimbolide, and 28-deoxonim-bolide. Analysis of tumor tissue and plasma samples from mice treated with SENL indicated 28-deoxonim-bolide and nimbolide as the bioactive compounds. Overall, our data revealed the bioactive compounds in SENL and suggested that the anticancer activity could be mediated through alteration in androgen receptor and calreticulin levels in prostate cancer.
doi:10.1158/1535-7163.MCT-13-0699
PMCID: PMC4308972  PMID: 24674886
2.  Nanoparticles for Combination Drug Therapy 
ACS nano  2013;7(11):9518-9525.
Nanoparticles have recently emerged as a promising class of carriers for the co-delivery of multiple drugs. Combination therapies of small-molecule drugs are common in clinical practice and it is anticipated that packaging into single macromolecular carriers will enable drug release in precisely balanced ratios and rates, and in selectively targeted tissues and cells. This vast level of pharmacological control is intriguing, especially from the perspective of tailoring personalized treatments with maximized therapeutic synergy for individual patients. Here, we discuss promising formulations and opportunities to employ advanced screening tools and new animal models of disease that can improve chances for successful clinical translation.
doi:10.1021/nn405674m
PMCID: PMC3894659  PMID: 24274814
3.  Exploratory study of a KLK2 polymorphism as a prognostic marker in prostate cancer 
Objectives
An association of a single nucleotide polymorphism (SNP) of the KLK2 gene (rs198977; c.748C>T; R250W) with risk for developing prostate cancer has been observed. We evaluated the role of R250W SNP for prognosis in prostate cancer.
Methods
The c.748C>T SNP was genotyped from blood DNA of 182 patients after completing initial cancer treatments. For evaluating prognosis of genotype groups, associations were performed with Gleason score (GS) and biochemical recurrence free survival (bRFS) in patients demonstrating PSA-recurrence after initial cancer therapy.
Results
Overall distribution of the CC, CT and TT genotypes for the SNP was 48%, 44% and 8%, respectively. The distribution of high (8–10), moderate (5–7) and low (2–4) GS among the genotype groups was 17%, 74% and 9% for CC group compared to 25%, 74% and 1% for the CT/TT (P = 0.04). Median bRFS time for CT/TT group was 36.5 months compared to 44.5 months for the CC group (P = 0.16), while genotype groups combined with morphology revealed significantly different bRFS (P = 0.004).
Conclusions
This exploratory analysis in prostate cancer patients revealed the W allele of the KLK2 R250W SNP to be less likely associated with low GS morphology. Further studies will be needed to confirm this observation in larger cohorts.
doi:10.3233/CBM-2010-0152
PMCID: PMC3982319  PMID: 21178268
Prostatic neoplasm; kallikrein; polymorphism; prognosis
4.  eRNA: a graphic user interface-based tool optimized for large data analysis from high-throughput RNA sequencing 
BMC Genomics  2014;15:176.
Background
RNA sequencing (RNA-seq) is emerging as a critical approach in biological research. However, its high-throughput advantage is significantly limited by the capacity of bioinformatics tools. The research community urgently needs user-friendly tools to efficiently analyze the complicated data generated by high throughput sequencers.
Results
We developed a standalone tool with graphic user interface (GUI)-based analytic modules, known as eRNA. The capacity of performing parallel processing and sample management facilitates large data analyses by maximizing hardware usage and freeing users from tediously handling sequencing data. The module miRNA identification” includes GUIs for raw data reading, adapter removal, sequence alignment, and read counting. The module “mRNA identification” includes GUIs for reference sequences, genome mapping, transcript assembling, and differential expression. The module “Target screening” provides expression profiling analyses and graphic visualization. The module “Self-testing” offers the directory setups, sample management, and a check for third-party package dependency. Integration of other GUIs including Bowtie, miRDeep2, and miRspring extend the program’s functionality.
Conclusions
eRNA focuses on the common tools required for the mapping and quantification analysis of miRNA-seq and mRNA-seq data. The software package provides an additional choice for scientists who require a user-friendly computing environment and high-throughput capacity for large data analysis. eRNA is available for free download at https://sourceforge.net/projects/erna/?source=directory.
doi:10.1186/1471-2164-15-176
PMCID: PMC4029068  PMID: 24593312
RNA sequencing; Bioinformatics tool; Graphic user interface; Parallel processing
5.  Serum microRNA expression patterns that predict early treatment failure in prostate cancer patients 
Oncotarget  2014;5(3):824-840.
We aimed to identify microRNA (miRNA) expression patterns in the serum of prostate cancer (CaP) patients that predict the risk of early treatment failure following radical prostatectomy (RP). Microarray and Q-RT-PCR analyses identified 43 miRNAs as differentiating disease stages within 14 prostate cell lines and reflectedpublically available patient data. 34 of these miRNA were detectable in the serum of CaP patients. Association with time to biochemical progression was examined in a cohort of CaP patients following RP. A greater than two-fold increase in hazard of biochemical progression associated with altered expression of miR-103, miR-125b and miR-222 (p <.0008) in the serum of CaP patients. Prediction models based on penalized regression analyses showed that the levels of the miRNAs and PSA together were better at detecting false positives than models without miRNAs, for similar level of sensitivity. Analyses of publically available data revealed significant and reciprocal relationships between changes in CpG methylation and miRNA expression patterns suggesting a role for CpG methylation to regulate miRNA. Exploratory validation supported roles for miR-222 and miR-125b to predict progression risk in CaP. The current study established that expression patterns of serum-detectable miRNAs taken at the time of RP are prognostic for men who are at risk of experiencing subsequent early biochemical progression. These non-invasive approaches could be used to augment treatment decisions.
PMCID: PMC3996656  PMID: 24583788
Prostate cancer; microRNA; biochemical progression; miR-103; miR-125b; miR-222; cancer epigenetics
6.  An observational study of plasma vascular endothelial growth factors (VEGF) A and D expression in non-localized prostate cancer 
Journal of men's health  2012;9(3):182-189.
Background
The aim of the study was to measure plasma levels of the vascular endothelial growth factors (VEGF) A and D in serially collected blood specimens from non-localized prostate cancer (PCa) subjects.
Methods
Plasma VEGF A and D levels were measured in two serial specimens 3–6 months apart in two groups of non-localized stage PCa patients. Group 1 was comprised of patients with biochemical relapse after localized PCa treatments and/or patients with clinically metastatic hormone-sensitive stage PCa prior to receiving hormonal therapy. Group 2 included patients failing hormonal therapy for non-localized hormone-sensitive stage PCa. VEGF A and D levels were compared within each cancer group between the two time-points using the Wilcoxon Rank Sum test.
Results
At the first time-point in Group 1 (n = 46), median VEGF-A and D levels were measured at 5.2 (pg/ml) (range = 0–97) and 319 (range = 172–780) (pg/ml). For Group 2 (n = 34) VEGF-A level was 9.6 pg/ml (range = 0–78) and VEGF-D level was 377 pg/ml (range = 243–989) for the first measurement. Median time-period for the serial second specimen was 189 days in Group 1 and 84 days in Group 2. At the second time-point, in Group 1, VEGF-A levels were 0.0 pg/ml (P = 0.0002) while VEGF-D increased to 349 pg/ml (P = 0.002). For Group 2 patients at the second time-point, median VEGF-A was 0.0 pg/ml (P = 1.0) and VEGF-D was measured at 442 pg/ml (P = 0.008).
Conclusions
Higher plasma VEGF-D than VEGF-A expression in advanced PCa stages suggests a greater role for VEGF-D dependent lymph angiogenesis in advanced stage PCa, which needs further evaluation.
PMCID: PMC3886726  PMID: 24416090
Prostate cancer; Angiogenesis; VEGF; Chemo-hormonal treatments
7.  Cardiac Metastasis in Renal Cell Carcinoma without Vena Cava or Atrial Involvement: an Unusual Presentation of Metastatic Disease 
Rare Tumors  2013;5(3):e29.
Cardiac metastasis in renal cell carcinoma is a very rare entity, with only a few previously reported cases. In this series, we report two cases of ventricular metastases from renal cell carcinoma without vena cava or right atrial involvement. The first case involves an initially isolated inoperable metastasis to the left ventricle, which was treated with systemic targeted therapy with favorable local response. Our second case illustrates a patient with an isolated cardiac metastasis in the interventricular septum with extension into the right ventricle, which has also remained stable in size on systemic targeted therapy. Although anti-angiogenic agents such as tyrosine kinase inhibitors have transformed the treatment of metastatic renal cell carcinoma in recent years, their efficacy and safety in treating patients with metastatic disease in highly vascular organs such as the heart are currently unknown, with no prior reports on this topic. We describe our novel management of these unique cases and discuss the current medical and surgical approaches to treating cardiac metastases from renal cell carcinoma.
doi:10.4081/rt.2013.e29
PMCID: PMC3804804  PMID: 24179641
renal cell carcinoma; cardiac metastases; targeted therapy
8.  Characterization of human plasma-derived exosomal RNAs by deep sequencing 
BMC Genomics  2013;14:319.
Background
Exosomes, endosome-derived membrane microvesicles, contain specific RNA transcripts that are thought to be involved in cell-cell communication. These RNA transcripts have great potential as disease biomarkers. To characterize exosomal RNA profiles systemically, we performed RNA sequencing analysis using three human plasma samples and evaluated the efficacies of small RNA library preparation protocols from three manufacturers. In all we evaluated 14 libraries (7 replicates).
Results
From the 14 size-selected sequencing libraries, we obtained a total of 101.8 million raw single-end reads, an average of about 7.27 million reads per library. Sequence analysis showed that there was a diverse collection of the exosomal RNA species among which microRNAs (miRNAs) were the most abundant, making up over 42.32% of all raw reads and 76.20% of all mappable reads. At the current read depth, 593 miRNAs were detectable. The five most common miRNAs (miR-99a-5p, miR-128, miR-124-3p, miR-22-3p, and miR-99b-5p) collectively accounted for 48.99% of all mappable miRNA sequences. MiRNA target gene enrichment analysis suggested that the highly abundant miRNAs may play an important role in biological functions such as protein phosphorylation, RNA splicing, chromosomal abnormality, and angiogenesis. From the unknown RNA sequences, we predicted 185 potential miRNA candidates. Furthermore, we detected significant fractions of other RNA species including ribosomal RNA (9.16% of all mappable counts), long non-coding RNA (3.36%), piwi-interacting RNA (1.31%), transfer RNA (1.24%), small nuclear RNA (0.18%), and small nucleolar RNA (0.01%); fragments of coding sequence (1.36%), 5′ untranslated region (0.21%), and 3′ untranslated region (0.54%) were also present. In addition to the RNA composition of the libraries, we found that the three tested commercial kits generated a sufficient number of DNA fragments for sequencing but each had significant bias toward capturing specific RNAs.
Conclusions
This study demonstrated that a wide variety of RNA species are embedded in the circulating vesicles. To our knowledge, this is the first report that applied deep sequencing to discover and characterize profiles of plasma-derived exosomal RNAs. Further characterization of these extracellular RNAs in diverse human populations will provide reference profiles and open new doors for the development of blood-based biomarkers for human diseases.
doi:10.1186/1471-2164-14-319
PMCID: PMC3653748  PMID: 23663360
Exosome; microRNA; Next generation sequencing; Plasma; Biomarker
9.  The Relationship of the Intensity of Posttreatment Prostate-Specific Antigen Surveillance and Prostate Cancer Outcomes: Results From a Population-Based Cohort 
Mayo Clinic Proceedings  2012;87(6):540-547.
Objective
To determine whether higher intensity of prostate-specific antigen (PSA) surveillance was associated with earlier detection of biochemical recurrence (BCR) or survival.
Patients and Methods
We identified a population-based cohort of 832 men diagnosed with nonmetastatic prostate cancer between January 1, 1995, and July 31, 2006. These men were treated with radical prostatectomy (RP), brachytherapy or external beam radiation therapy (RT), or primary androgen deprivation therapy or chose watchful waiting. To test the associations of intensity in PSA surveillance with study outcomes, we used a 2-year landmark analysis to assess whether the number of PSA tests during the first 2 years after treatment was associated with earlier detection of BCR, prostate cancer–related mortality, and all-cause mortality. We used landmark analysis to assess the association of PSA intensity, adjusting for clinicopathologic covariate, with outcome.
Results
Median follow-up time for the entire cohort was 6.7 years. Higher Gleason score was the only clinicopathologic variable associated with higher PSA frequency in multivariable analysis for both the RP and RT groups (P value of .001 and .05, respectively). After adjustment for other covariates, the frequency of PSA tests during the first 2 years after RP did not increase the ability to detect BCR (hazard ratio, 1.00; 95% confidence interval, 0.84-1.19) or all-cause mortality (hazard ratio, 0.95; 95% confidence interval, 0.70-1.30) in the landmark analysis.
Conclusion
Higher intensity of PSA surveillance during the 2 years after RP or RT did not improve earlier detection of BCR or survival. Evidence-based guidelines for PSA surveillance after primary treatment are needed.
doi:10.1016/j.mayocp.2012.01.017
PMCID: PMC3498058  PMID: 22677074
ACM, all-cause mortality; ADT, androgen deprivation therapy; BCR, biochemical recurrence; HR, hazard ratio; PCSM, prostate cancer–specific mortality; PSA, prostatic-specific antigen; RP, radical prostatectomy; RT, radiation therapy; WW, watchful waiting
10.  Germline Predictors of Androgen Deprivation Therapy Response in Advanced Prostate Cancer 
Mayo Clinic Proceedings  2012;87(3):240-246.
Objective
To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response.
Patients and Methods
In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing.
Results
At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less.
Conclusion
Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.
doi:10.1016/j.mayocp.2011.09.009
PMCID: PMC3538410  PMID: 22386179
11.  Biomarker-Based Targeting of the Androgen-Androgen Receptor Axis in Advanced Prostate Cancer 
Advances in Urology  2012;2012:781459.
Recent therapeutic advances for managing advanced prostate cancer include the successful targeting of the androgen-AR axis with several new drugs in castrate resistant prostate cancer including abiraterone acetate and enzalutamide (MDV3100). This translational progress from “bench to bed-side” has resulted in an enlarging repertoire of novel and traditional drug choices now available for use in advanced prostate cancer therapeutics, which has had a positive clinical impact in prolonging longevity and quality of life of advanced prostate cancer patients. In order to further the clinical utility of these drugs, development of predictive biomarkers guiding individual therapeutic choices remains an ongoing challenge. This paper will summarize the potential in developing predictive biomarkers based on the pathophysiology of the androgen-AR axis in tumor tissue from patients with advanced prostate cancer as well as inherited variation in the patient's genome. Specific examples of rational clinical trial designs incorporating potential predictive biomarkers from these pathways will illustrate several aspects of pharmacogenetic and pharmacogenomic predictive biomarker development in advanced prostate cancer therapeutics.
doi:10.1155/2012/781459
PMCID: PMC3432332  PMID: 22956944
12.  Novel Molecular Targets of Azadirachta indica Associated with Inhibition of Tumor Growth in Prostate Cancer 
The AAPS Journal  2011;13(3):365-377.
Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models. Analysis of the components in the EENL by mass spectrometry suggests the presence of 2′,3′-dehydrosalannol, 6-desacetyl nimbinene, and nimolinone. Treatment of C4-2B and PC-3M-luc2 prostate cancer cells with EENL inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with EENL treatment in prostate cancer cells. Functional analysis unveiled that most of the up-regulated genes were associated with cell death, and drug metabolism, and the down-regulated genes were associated with cell cycle, DNA replication, recombination, and repair functions. Quantitative PCR confirmed significant up-regulation of 40 genes and immunoblotting revealed increase in the protein expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10. EENL treatment inhibited the growth of C4-2B and PC-3M-luc2 prostate cancer xenografts in nude mice. The suppression of tumor growth is associated with the formation of hyalinized fibrous tumor tissue and the induction of cell death by apoptosis. These results suggest that EENL-containing natural bioactive compounds could have potent anticancer property and the regulation of multiple cellular pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-011-9279-4) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-011-9279-4
PMCID: PMC3144372  PMID: 21560017
gene expression profiles; neem leaf extract; therapeutic targets and prostate cancer; tumor models
13.  Androgen deprivation therapy-associated vasomotor symptoms 
Asian Journal of Andrology  2012;14(2):193-197.
Androgen deprivation therapy (ADT) is widely used as standard therapy in the treatment of locally advanced and metastatic prostate cancer. While efficacious, ADT is associated with multiple side effects, including decreased libido, erectile dysfunction, diabetes, loss of muscle tone and altered body composition, osteoporosis, lipid changes, memory loss, gynecomastia and hot flashes. The breadth of literature for the treatment of hot flashes is much smaller in men than that in women. While hormonal therapy of hot flashes has been shown to be effective, multiple non-hormonal medications and treatment methods have also been developed. This article reviews current options for the treatment of hot flashes in patients taking ADT.
doi:10.1038/aja.2011.101
PMCID: PMC3338189  PMID: 22286861
androgen deprivation therapy; hot flashes; vasomotor symptoms
14.  Androgen deprivation therapy-associated vasomotor symptoms 
Asian Journal of Andrology  2012;14(2):193-197.
Androgen deprivation therapy (ADT) is widely used as standard therapy in the treatment of locally advanced and metastatic prostate cancer. While efficacious, ADT is associated with multiple side effects, including decreased libido, erectile dysfunction, diabetes, loss of muscle tone and altered body composition, osteoporosis, lipid changes, memory loss, gynecomastia and hot flashes. The breadth of literature for the treatment of hot flashes is much smaller in men than that in women. While hormonal therapy of hot flashes has been shown to be effective, multiple non-hormonal medications and treatment methods have also been developed. This article reviews current options for the treatment of hot flashes in patients taking ADT.
doi:10.1038/aja.2011.101
PMCID: PMC3338189  PMID: 22286861
androgen deprivation therapy; hot flashes; vasomotor symptoms
15.  Antiangiogenic Effects and Therapeutic Targets of Azadirachta indica Leaf Extract in Endothelial Cells 
Azadirachta indica (common name: neem) leaves have been found to possess immunomodulatory, anti-inflammatory and anti-carcinogenic properties. The present study evaluates anti-angiogenic potential of ethanol extract of neem leaves (EENL) in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with EENL inhibited VEGF induced angiogenic response in vitro and in vivo. The in vitro proliferation, invasion and migration of HUVECs were suppressed with EENL. Nuclear fragmentation and abnormally small mitochondria with dilated cristae were observed in EENL treated HUVECs by transmission electron microscopy. Genome-wide mRNA expression profiling after treatment with EENL revealed differentially regulated genes. Expression changes of the genes were validated by quantitative real-time polymerase chain reaction. Additionally, increase in the expression of HMOX1, ATF3 and EGR1 proteins were determined by immunoblotting. Analysis of the compounds in the EENL by mass spectrometry suggests the presence of nimbolide, 2′,3′-dehydrosalannol, 6-desacetyl nimbinene and nimolinone. We further confirmed antiproliferative activity of nimbolide and 2′,3′-dehydrosalannol in HUVECs. Our results suggest that EENL by regulating the genes involved in cellular development and cell death functions could control cell proliferation, attenuate the stimulatory effects of VEGF and exert antiangiogenic effects. EENL treatment could have a potential therapeutic role during cancer progression.
doi:10.1155/2012/303019
PMCID: PMC3296311  PMID: 22461839
16.  Thrombin Expression in Prostate: A Novel Finding 
Cancer investigation  2011;29(1):62-67.
Introduction
A variable repertoire of coagulation protein expression is observed in different cancers. We evaluated expression of thrombin in prostate tissue.
Methods
Detection of thrombin was performed using quantitative real-time PCR in fresh tissue and in situ hybridization (ISH) in archival prostate tissue and by immunohistochemistry of prostate tissue microarrays.
Results
(Pro)thrombin mRNA expression was detected in cancer tissue and localized to prostatic epithelium and stroma by ISH. Thrombin protein was detected in stroma of benign and malignant epithelium (p <.05).
Conclusions
Prostate tissue is a rich reservoir of thrombin. This may have potential for developing antithrombin-based cancer therapy.
doi:10.3109/07357907.2010.535057
PMCID: PMC3136353  PMID: 21166500
Prostatic neoplasms; Prothrombin; Coagulation
17.  Novel Molecular Targets of Azadirachta indica Associated with Inhibition of Tumor Growth in Prostate Cancer 
The AAPS Journal  2011;13(3):365-377.
Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models. Analysis of the components in the EENL by mass spectrometry suggests the presence of 2′,3′-dehydrosalannol, 6-desacetyl nimbinene, and nimolinone. Treatment of C4-2B and PC-3M-luc2 prostate cancer cells with EENL inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with EENL treatment in prostate cancer cells. Functional analysis unveiled that most of the up-regulated genes were associated with cell death, and drug metabolism, and the down-regulated genes were associated with cell cycle, DNA replication, recombination, and repair functions. Quantitative PCR confirmed significant up-regulation of 40 genes and immunoblotting revealed increase in the protein expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10. EENL treatment inhibited the growth of C4-2B and PC-3M-luc2 prostate cancer xenografts in nude mice. The suppression of tumor growth is associated with the formation of hyalinized fibrous tumor tissue and the induction of cell death by apoptosis. These results suggest that EENL-containing natural bioactive compounds could have potent anticancer property and the regulation of multiple cellular pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-011-9279-4) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-011-9279-4
PMCID: PMC3144372  PMID: 21560017
gene expression profiles; neem leaf extract; therapeutic targets and prostate cancer; tumor models
18.  Multiple urinary bladder masses from metastatic prostate adenocarcinoma 
Rare Tumors  2010;2(4):e65.
We present an unusual case of metastatic prostate adenocarcinoma that manifested with multiple exophytic intravesical masses, mimicking a multifocal primary bladder tumor. Biopsy with immunohistochemical analysis confirmed metastatic prostate adenocarcinoma. The patient was treated palliatively with external beam radiotherapy to prevent possible symptoms from local tumor progression. This case illustrates that when a patient with known prostate cancer presents with multifocal bladder tumors, the possibility of metastatic prostate cancer should be considered.
doi:10.4081/rt.2010.e65
PMCID: PMC3019600  PMID: 21234257
urinary bladder neoplasms; prostatic neoplasms; radiotherapy.
19.  New Developments in the Medical Management of Prostate Cancer 
Mayo Clinic Proceedings  2010;85(1):77-86.
Prostate cancer is a substantial public health burden and a leading cause of cancer—related morbidity and mortality in the United States despite the observation that annual prostate cancer—specific mortality rates have been declining during the previous decade. Although the reasons for this positive development are unclear, a combination of factors may have contributed. This update will review ongoing developments and summarize therapeutic advances in prostate cancer treatment on the basis of the current understanding of prostate cancer biology. Literature for this review was selected in 2009 by searching PubMed for the following keywords: prostatic neoplasms, castration, androgen receptor, hormonal, and chemotherapy. Emphasis is placed on published clinical studies in advanced prostate cancer therapeutics in the past 5 to 10 years. Also included in the review are novel hormonal agents targeting the androgen receptor currently in development for the treatment of advanced prostate cancer.
doi:10.4065/mcp.2009.0442
PMCID: PMC2800284  PMID: 20042563

Results 1-19 (19)