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The nuclear transport protein Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is over-expressed 2- 4 fold in cancer. XPO1 is one of seven nuclear exporter proteins, and is solely responsible for the transport of the major tumor suppressor proteins (TSPs) from the nucleus to the cytoplasm. XPO1 exports any protein that carries a leucine-rich, hydrophobic nuclear export sequence (NES). A number of inhibitors have been discovered that block XPO1 function and thereby restore TSPs to the nucleus of both malignant and normal cells. However, natural product, irreversible XPO1 antagonists such as leptomycin B (LMB) have proven toxic in both preclinical models and in the clinic. Recently, orally bioavailable, drug-like small molecule, potent and selective inhibitors of XPO1 mediated nuclear export ("SINE") have been designed and are undergoing clinical evaluations in both humans and canines with cancer. The breadth of clinical applicability and long-term viability of an XPO1 inhibition strategy requires a deeper evaluation of the consequence of global re-organization of proteins in cancer and normal cells. Unfortunately, most of the studies on XPO1 inhibitors have focused on evaluating a limited number of TSPs or other proteins. Because XPO1 carries ~220 mammalian proteins out of the nucleus, such reductionism has not permitted a global understanding of cellular behavior upon drug-induced disruption of XPO1 function. The consequence of XPO1 inhibition requires holistic investigations that consider the entire set of XPO1 targets and their respective pathways modulated without losing key details. Systems biology is one such holistic approach that can be applied to understand XPO1 regulated proteins along with the downstream players involved. This review provides comprehensive evaluations of the different computational tools that can be utilized in the better understanding of XPO1 and its target. We anticipate that such holistic approaches can allow for the development of a clinically successful XPO1 targeted therapeutic strategy against cancer.

MicroRNAs (miRNAs) are short non-coding RNAs that have been recognized to regulate the expression of uncountable number of genes. Their aberrant expression has been found to be linked to the pathology of many diseases including cancer. There is a drive to develop miRNA targeted therapeutics for different diseases especially cancer. Nevertheless, reining in these short non-coding RNAs is not as straightforward as originally thought. This is in view of the recent discoveries that miRNAs are under epigenetic regulations at multiple levels. Exportin 5 protein (XPO5) nuclear export mediated regulation of miRNAs is one such important epigenetic mechanism. XPO5 is responsible for exporting precursor miRNAs through the nuclear membrane to the cytoplasm, and is thus a critical step in miRNA biogenesis. A number of studies have shown that variations in components of the miRNA biogenesis pathways, particularly the aberrant expression of XPO5, increase the risk of developing cancer. In addition to XPO5, the Exportin 1 protein (XPO1) or chromosome region maintenance 1 (CRM1) can also carry miRNA export function. These findings are supported by pathway analyses that reveal certain miRNAs as direct interaction partners of CRM1. An in depth understanding of miRNA export mediated regulatory mechanisms is important for the successful design of clinically viable therapeutics. In this review, we describe the current knowledge on the mechanisms of miRNA nuclear transport mediated regulation and propose strategies to selectively block this important mechanism in cancer.

The theory of cancer stem cells (CSCs) has provided evidence on fundamental clinical implications because of the involvement of CSCs in cell migration, invasion, metastasis, and treatment resistance, which leads to the poor clinical outcome of cancer patients. Therefore, targeting CSCs will provide a novel therapeutic strategy for the treatment and/or prevention of tumors. However, the regulation of CSCs and its signaling pathways during tumorigenesis are not well understood. MicroRNAs (miRNAs) have been proved to act as key regulators of the post-transcriptional regulation of genes, which involve in a wide array of biological processes including tumorigenesis. The altered expressions of miRNAs are associated with poor clinical outcome of patients diagnosed with a variety of tumors. Therefore, emerging evidence strongly suggest that miRMAs play critical roles in tumor development and progression. Emerging evidence also suggest that miRNAs participate in the regulation of tumor cell growth, migration, invasion, angiogenesis, drug resistance, and metastasis. Moreover, miRNAs such as let-7, miR-21, miR-22, miR-34, miR-101, miR-146a, and miR-200 have been found to be associated with CSC phenotype and function mediated through targeting oncogenic signaling pathways. In this article, we will discuss the role of miRNAs in the regulation of CSC phenotype and function during tumor development and progression. We will also discuss the potential role of naturally occurring agents (nutraceuticals) as potent anti-tumor agents that are believed to function by targeting CSC-related miRNAs.

Resveratrol found in fruits, vegetables and beverages such as red wine, has been extensively evaluated for its anticardiovascular disease and cancer preventive effects. Even though studies have demonstrated its anti-tumor effects, there is still no clear explanation for cancer cell selective mechanisms of action of resveratrol. Initial investigations were focused on its anti-oxidant and cytoprotective mechanism of action, yet, a large number of studies have demonstrated that resveratrol can behave either as anti-oxidant or pro-oxidant depending on the selective microenvironment. What makes resveratrol a protective agent in normal cells and a radical generator possessing cytotoxic activity against cancer cells is a widely debated topic. There must be certain conditions found in tumors that allow resveratrol to become a pro-oxidant that clearly differs from that found in normal cells. Results of studies from our group have established that many different dietary agents can mobilize intracellular copper ions and in the process, generate reactive oxygen species through Fenton type reactions leading to oxidative DNA breakage and consequently, cell death. More significantly, we demonstrated that such pro-oxidant-induced DNA damage and apoptotic activity are enhanced in low pH environments; characteristically observed in tumors due to preferential dependence on glycolysis or the "Warburg effect". This review discusses the recent advancements in understanding the pro-oxidant anti-cancer behavior of resveratrol as a dietary chemopreventive agent, explained in the light of the Warburg effect.

Diabetes mellitus categorized as type I and II, is a disease of pancreatic insulin, affecting blood glucose level in the body. Recent evidence suggests that cardiac diseases such as hypertension, coronary artery disease, congestive heart failure, and diabetic cardiomyopathy are associated with diabetes and hyperglycemia. The adenosine receptors (AR) have been reported to play an important role in the regulation of these diseases. Four adenosine receptors have been cloned and characterized from several different mammalian species. The receptors are named adenosine A 1 , A 2 A, A 2 B, and A 3 . The A 2 A and A 2 B receptors preferably interact with members of the Gs family of G proteins and the A 1 and A 3 receptors with Gi/o proteins. The ubiquitous levels of adenosine are found in each cell in normal conditions but in disease conditions its level has been shown to increase and activate G-protein mediated signaling pathway leading to artery constriction in cardiovascular diseases and diabetes. Various studies have demonstrated that A 3 AR is a potent cardioprotectant during myocardial ischemeia/ischemic reperfusion. Role of A3AR receptor as a possible cardioprotectant in diabetes is under investigation and studies have verified the involvement of cyclooxygenases (COXs) and NADPH oxidase pathways. This review summarizes the possible role of A 3 AR in cardiovascular disease and discusses advancement in the development of therapeutic agents targeting cardioprotection with discussion on recent patents on A 3 agonists that are being utilized in the clinical setting. We anticipate that detailed pharmacological studies of adenosine A 3 receptors could help in understanding the link between cardiovascular disease and diabetes and this can be utilized to develop newer therapies that selectively target A 3 receptor to overcome cardiac challenges.

The discovery of small molecule inhibitors of HDM2-p53 interaction is considered one of the most significant therapeutic developments in the area p53 research. Intensive work on different classes of HDM2 inhibitors has proven their therapeutic utility as activators of p53 in multiple tumor models. Many laboratories have shown that HDM2 inhibitors can synergize with chemotherapeutic agents resulting in enhanced efficacy through both p53-dependent and independent mechanisms. In our hands HDM2 inhibitor and platinum drug combination showed remarkable antitumor activity that led tumor free survival in one of the most resistant and complex pancreatic xenograft models. Although antitumor efficacy of such combinations has been studied in detail, not much is known on the molecular mechanisms governing this synergy. This is partly due to complexity of multiple pathways modulated by p53 and HDM2. We are of the view that in order to decode this complexity, an integrated approach is needed that considers both HDM2 and p53 as components of a network and not in isolation. This review highlights recent advancements in our understanding of HDM2 inhibitor combination therapy based on network modeling and systems biology driven science. Our recent findings support such a network view as integrated gene expression profiling and pathway network modeling on MI-219-oxaliplatin treated cells revealed activation of multiple and closely knit biological networks. We anticipate that in the near future such network-centric approaches will benefit clinical development of HDM2 inhibitors for genetically predefined subsets of cancer patients and this will be a step towards personalized medicine.