Barbara B. Doonan

Functional/Activity Network (FAN) Analysis of Gene-Phenotype Connectivity Liaised by Grape Polyphenol Resveratrol

Resveratrol is a polyphenol that has witnessed an unprecedented yearly growth in PubMed citations since the late 1990s. Based on the diversity of cellular processes and diseases resveratrol reportedly affects and benefits, it is likely that the interest in resveratrol will continue, although uncertainty regarding its mechanism in different biological systems remains. We hypothesize that insights on disease-modulatory activities of resveratrol might be gleaned by systematically dissecting the publicly available published data on chemicals and drugs. In this study, we tested our hypothesis by querying DTome (Drug-Target Interactome), a web-based tool containing data compiled from open-source databases including DrugBank, PharmGSK, and Protein Interaction Network Analysis (PINA). Four direct protein targets (DPT) and 219 DPT-associated genes were identified for resveratrol. The DPT-associated genes were scrutinized by WebGestalt (WEB-based Gene SeT Analysis Toolkit). This enrichment analysis resulted in 10 identified KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. Refined analysis of KEGG pathways showed that 2 — one linked to p53 and a second to prostate cancer — have functional connectivity to resveratrol and its four direct protein targets. These results suggest that a functional activity network (FAN) approach may be considered as a new paradigm for guiding future studies of resveratrol. FAN analysis resembles a BioGPS, with capability for mapping a Web-based scientific track that can productively and cost effectively connect resveratrol to its primary and secondary target proteins and to its biological functions.

Anticancer Activities of Resveratrol in Colorectal Cancer

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a dietary polyphenolic phytochemical that has demonstrated health benefits such as cardioprotection, the prevention of neurodegeneration and chemoprevention. Resveratrol has shown great potential in the prevention and treatment of carcinomas and clinical trials support resveratrol as anticancer compound in colorectal carcinoma. Colorectal cancer remains a major cause of cancer-related deaths for both men and women in industrialized countries. Because of this widespread prevalence, identifying major risk factors and initiating colorectal screening procedures provide the distinct advantage for recognizing early disease and addressing treatable forms of CRC. Epidemiological studies of fruit and vegetable consumption in relationship to developing CRC have led to the notion that safe and inexpensive chemopreventive agents might be a valuable tool in diminishing the morbidity and mortality of CRC. While clinical trials and in vivo data show positive effects of resveratrol in CRC, the mechanism of action is relatively unclear. In this review, we will evaluate the current literature on the actions of resveratrol in CRC and provide a more mechanistic view of resveratrol in relationship with CRC.

Application of Open-Access Databases to Determine Functional Connectivity Between Resveratrol-Binding Protein QR2 and Colorectal Carcinoma

Colorectal cancer (CRC) is a major cause of cancer-associated deaths worldwide. Recently, oral administration of resveratrol (trans-3,5,4′-trihydroxystilbene) has been reported to significantly reduce tumor proliferation in colorectal cancer patients, however, with little specific information on functional connections. The pathogenesis and development of colorectal cancer is a multistep process that can be categorized using three phenotypic pathways, respectively, chromosome instability (CIN), microsatellite instability (MSI), and CpG island methylator (CIMP). Targets of resveratrol, including a high-affinity binding protein, quinone reductase 2 (QR2), have been identified with little information on disease association. We hypothesize that the relationship between resveratrol and different CRC etiologies might be gleaned using publicly available databases. A web-based microarray gene expression data-mining platform, Oncomine, was selected and used to determine whether QR2 may serve as a mechanistic and functional biotarget within the various CRC etiologies. We found that QR2 messenger RNA (mRNA) is overexpressed in CRC characterized by CIN, particularly in cells showing a positive KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation, as well as by the MSI but not the CIMP phenotype. Mining of Oncomine revealed an excellent correlation between QR2 mRNA expression and certain CRC etiologies. Two resveratrol-associated genes, adenomatous polyposis coli (APC) and TP53, found in CRC were further mined, using cBio portal and Colorectal Cancer Atlas which predicted a mechanistic link to exist between resveratrol→QR2/TP53→CIN. Multiple web-based data mining can provide valuable insights which may lead to hypotheses serving to guide clinical trials and design of therapies for enhanced disease prognosis and patient survival. This approach resembles a BioGPS, a capability for mining web-based databases that can elucidate the potential links between compounds to provide correlations of these interactions with specific diseases.

BRAF Mutation in Melanoma and Dietary Polyphenols as Adjunctive Treatment Strategy

Melanomas are the most insidious type of skin cancers, with more than 76,000 new cases and over 9100 deaths anticipated by 2013 in the United States. Recent advances in an understanding of genetic alterations that cause mutations in the oncogenes BRAF and NRAS, have provided new leads for treatment of melanoma. A valine-to-glutamic acid substitution mutation at position 600 (V600E) in the BRAF kinase gene has been shown to occur in approximately 75% melanoma cases. This mutation results in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, thus offering a target amenable to development of novel therapies and to adjunctive or complementary management options. A number of preclinical and clinical investigations of small molecule inhibitors of BRAF show promise, e.g., Zelboraf, an FDA-approved BRAF inhibitor for the treatment of metastatic melanomas with the V600E mutation. However, drug resistance has been found to occur in some patients. Elucidating possible mechanisms behind resistance and developing therapies to bypass such are important in ensuring the success of BRAF inhibitors. BRAF is strategically positioned at the tip of a signaling cascade that transduces effects through a cadre of downstream targets. Several studies show that these proteins are negatively regulated by a variety of diet-derived polyphenols and suggest that an intervention “cocktail” comprising these components may play be considered for development as “low bioactivity-less resistance inducing” adjunctive treatment of melanoma.

Molecular Sensors and Mediators of Skin Cancer Preventative Phytochemicals

Skin cancer, a leading cause of cancer deaths in the US population, lacks treatment options when the disease relapses at local or distant sites.

CHAPTER 33:Prevention and Management of Obesity by Isoflavones

Obesity is a metabolic disease that is increasing in potentially epidemic proportions in the United States and throughout the world. Because obesity is clinically presented as manifestation of several degenerative disorders such as coronary heart disease, hypertension and type 2 diabetes, a uniformly safe and effective therapeutic regimen is as yet unavailable. The mainstay of pharmacological intervention for obesity includes suppression of appetite to curtail food intake or increased disposal of calories in the stool. Lifestyle factors including diet and nutrition may positively or adversely affect the risk of obesity. This Chapter will review evidence regarding the dietary intake of soy and soy isoflavones as an additional consideration for preventing and managing obesity. We will evaluate results obtained from a combination of laboratory, animal and population-based studies relevant to molecular and cellular control of adipogenesis. We will present and discuss the salient features of an approach aimed at identifying soy isoflavones with anti-obesity potentials. We will also explore mechanistic links between dietary habits and the development of obesity, and consumption of isoflavones that might account for their anti-obesity effects.