Vitamin D, Sunlight and Prostate Cancer Risk

Prostate cancer is the second common cancer in men worldwide. The prevention of prostate cancer remains a challenge to researchers and clinicians. Here, we review the relationship of vitamin D and sunlight to prostate cancer risk. Ultraviolet radiation of the sunlight is the main stimulator for vitamin D production in humans. Vitamin D's antiprostate cancer activities may be involved in the actions through the pathways mediated by vitamin D metabolites, vitamin D metabolizing enzymes, vitamin D receptor (VDR), and VDR-regulated genes. Although laboratory studies including the use of animal models have shown that vitamin D has antiprostate cancer properties, whether it can effectively prevent the development and/or progression of prostate cancer in humans remains to be inconclusive and an intensively studied subject. This review will provide up-to-date information regarding the recent outcomes of laboratory and epidemiology studies on the effects of vitamin D on prostate cancer prevention

Oxidative Stress and DNA Methylation in Prostate Cancer

The protective effects of fruits, vegetables, and other foods on prostate cancer may be due to their antioxidant properties. An imbalance in the oxidative stress/antioxidant status is observed in prostate cancer patients. Genome oxidative damage in prostate cancer patients is associated with higher lipid peroxidation and lower antioxidant levels. Oxygen radicals are associated with different steps of carcinogenesis, including structural DNA damage, epigenetic changes, and protein and lipid alterations. Epigenetics affects genetic regulation, cellular differentiation, embryology, aging, cancer, and other diseases. DNA methylation is perhaps the most extensively studied epigenetic modification, which plays an important role in the regulation of gene expression and chromatin architecture, in association with histone modification and other chromatin-associated proteins. This review will provide a broad overview of the interplay of oxidative stress and DNA methylation, DNA methylation changes in regulation of gene expression, lifestyle changes for prostate cancer prevention, DNA methylation as biomarkers for prostate cancer, methods for detection of methylation, and clinical application of DNA methylation inhibitors for epigenetic therapy

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

Batch effect correction for genome-wide methylation data with Illumina Infinium platform

<p>Abstract</p> <p>Background</p> <p>Genome-wide methylation profiling has led to more comprehensive insights into gene regulation mechanisms and potential therapeutic targets. Illumina Human Methylation BeadChip is one of the most commonly used genome-wide methylation platforms. Similar to other microarray experiments, methylation data is susceptible to various technical artifacts, particularly batch effects. To date, little attention has been given to issues related to normalization and batch effect correction for this kind of data.</p> <p>Methods</p> <p>We evaluated three common normalization approaches and investigated their performance in batch effect removal using three datasets with different degrees of batch effects generated from HumanMethylation27 platform: quantile normalization at average β value (QNβ); two step quantile normalization at probe signals implemented in "lumi" package of R (lumi); and quantile normalization of A and B signal separately (ABnorm). Subsequent Empirical Bayes (EB) batch adjustment was also evaluated.</p> <p>Results</p> <p>Each normalization could remove a portion of batch effects and their effectiveness differed depending on the severity of batch effects in a dataset. For the dataset with minor batch effects (Dataset 1), normalization alone appeared adequate and "lumi" showed the best performance. However, all methods left substantial batch effects intact in the datasets with obvious batch effects and further correction was necessary. Without any correction, 50 and 66 percent of CpGs were associated with batch effects in Dataset 2 and 3, respectively. After QNβ, lumi or ABnorm, the number of CpGs associated with batch effects were reduced to 24, 32, and 26 percent for Dataset 2; and 37, 46, and 35 percent for Dataset 3, respectively. Additional EB correction effectively removed such remaining non-biological effects. More importantly, the two-step procedure almost tripled the numbers of CpGs associated with the outcome of interest for the two datasets.</p> <p>Conclusion</p> <p>Genome-wide methylation data from Infinium Methylation BeadChip can be susceptible to batch effects with profound impacts on downstream analyses and conclusions. Normalization can reduce part but not all batch effects. EB correction along with normalization is recommended for effective batch effect removal.</p

Current Treatment Strategies for Castration-Resistant Prostate Cancer

Prostate cancer is the most common cancer in men in United States and the fifth most common cancer in men in Korea. Although the majority of patients with metastatic prostate cancer initially respond to androgen deprivation therapy, almost all patients will eventually progress to develop castration-resistant prostate cancer (CRPC). Treatment options for CRPC remain limited. Prostate cancer was considered unresponsive to chemotherapy until the mid-1990s, when mitoxantrone combined with prednisone was shown to play a role in the palliative treatment of patients with CRPC. In 2004, two large randomized clinical trials demonstrated for the first time a small but significant survival advantage of docetaxel-based chemotherapy compared with mitoxantrone in patients with metastatic CRPC. Recently, cabazitaxel was shown to improve survival in patients with metastatic CRPC who progressed after docetaxel-based chemotherapy. Sipuleucel-T was also demonstrated to improve overall survival in patients with asymptomatic or minimally symptomatic metastatic CRPC. Along with mitoxantrone and docetaxel, cabazitaxel and sipuleucel-T are now approved for use in metastatic CRPC by the US Food and Drug Administration. There have been multiple early-phase clinical trials of various agents for the treatment of CRPC, and some are in phase III development. This review focuses on the key clinical trials of various treatment options of CRPC currently in use and under investigation

A Facile and Cost-effective Electroanalytical Strategy for the Quantification of Deoxyguanosine and Deoxyadenosine in Oligonucleotides Using Screen-printed Graphite Electrodes

The development of electroanalytical methods for the detection and quantification of nucleotides in DNA offers vital implications in assessing the degree of oxidation or epigenetic modification in DNA. Unfortunately, the electrochemical response of oligonucleotides is strongly influenced by the size, composition and nucleic base sequence. In this article, an optimized analytical procedure for the enzymatically breakdown of the oligonucleotides to their corresponding nucleotides for the evaluation of the electrochemical response through the use of square wave voltammetry (SWV) is presented. Enzymatic digestion of oligonucleotides has been optimized in terms of buffer composition, digestion time, strategy for stopping the enzymatic reaction and filtration requirement for enzyme removal, and then compared to an established protocol. Under the optimized protocol SWV response of a number of untreated and enzymatically digested six-mer oligonucleotides, namely 5′-GGGGGG-3′, 5′-AAAAAA-3′, 5′-CGCGCG-3′ and 5′-AAACGC-3′ have been analysed, providing a higher sensitivity for the determination of guanosine and adenosine monophosphate species under digestion conditions with a more facile and cost effective procedure. The novel strategy for the enzymatically treated oligonucleotides in combination with the SWV response provides a proof of principle for feasible applications in the diagnosis of methylated guanosine in DNA as a potential biomarker due to its relation with cancer

Novel Molecular Targets of Azadirachta indica Associated with Inhibition of Tumor Growth in Prostate Cancer

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