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- Volume 8, Issue 7, 2008
Current Cancer Drug Targets - Volume 8, Issue 7, 2008
Volume 8, Issue 7, 2008
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The Protein Acetyltransferase ARD1: A Novel Cancer Drug Target?
Authors: Thomas Arnesen, Paul R. Thompson, Jan E. Varhaug and Johan R. LillehaugEvasion of apoptosis and active cell proliferation are among the characteristics of cancer cells. Triggering the induction of apoptosis or reducing the proliferative rate will potentially be helpful for cancer treatment. Recently, several reports demonstrated that knockdown of the protein acetyltransferase hARD1 significantly reduced the growth rate of human cancer cell lines. Furthermore, hARD1 knockdown induced apoptosis or sensitized cells to drug induced apoptosis. hARD1 acts in complex with the NATH protein and catalyzes cotranslational acetylation of protein N-termini. Thus, it was suggested that the effects on cell proliferation and apoptosis induction are due to a reduced level of N-terminal acetylation of certain substrate proteins. NATH was originally identified as upregulated in thyroid papillary carcinomas and has lately also been found to correlate with aggressiveness and differentiation status of neuroblastic tumours. On the other hand, researchers recently reported that hARD1 acetylates Beta-catenin. Knockdown of hARD1 reduced the transcriptional activity of the Beta-Catenin/TCF4 complex, downregulating cyclin D1 and thereby promoting G1-arrest and inhibition of cell proliferation of lung cancer cells. Although the underlying molecular mechanisms need further clarification, several reports suggest that reduction of hARD1 negatively affects cell growth. Thus, hARD1 or the hARD1-NATH complex stands out as attractive drug targets in cancer treatment. One challenge will be to develop specific inhibitors that discriminate between hARD1 and the many other enzymes, including the histone acetyltransferases, using acetyl-coenzyme A as acetyl donor. This review focuses on the enzymatic and biological activities of hARD1, and potential mechanisms of functional inhibition.
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Cell-Specific Induction of Apoptosis by Rationally Designed Bivalent Aptamer-siRNA Transcripts Silencing Eukaryotic Elongation Factor 2
Authors: Ulrich Wullner, Inga Neef, Andreas Eller, Michael Kleines, Mehmet K. Tur and Stefan BarthNew strategies for cell type-specific delivery need to be developed if RNA interference is to realize its full therapeutic potential. One possible approach is the use of aptamers to deliver siRNAs selectively to tumor cells with appropriate antigens displayed on the surface. We used an aptamer that binds specifically to PSMA, a cell surface glycoprotein found in abundance on prostate cancer cells, and joined its 3' end to a siRNA specific for Eukaryotic Elongation Factor 2 mRNA (EEF2). This is an attractive target for cancer therapy because inhibiting EEF2 causes the rapid arrest of protein synthesis, inducing apoptosis and leading ultimately to cell death. In order to enhance the therapeutic efficacy of the aptamer-siRNA, we increased the valency of the construct by rational design. Two anti-PSMA aptamers were designed such that each binding sequence could fold independently into its active conformation. Here we show specific cytotoxicity resulting from siRNA-induced silencing of EEF2, as well as specific delivery to PSMA-expressing prostate cancer cells. Increasing the valency of the aptamer resulted in enhanced cytotoxicity compared with the monovalent constructs. The results presented here demonstrate the usefulness of multivalent aptamer-based delivery vehicles for siRNA therapeutics.
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Notch Signaling: A Potential Therapeutic Target in Prostate Cancer
Authors: M. A. Villaronga, C. L. Bevan and B. BelandiaThe Notch pathway and the endocrine system constitute two key biological signaling mechanisms, responsible for cell-to-cell communication between adjacent cells and long-distance hormonal signals respectively. They play central roles during the development of higher eukaryotic organisms but they also take part in the regulation of many aspects of adult physiology and homeostasis. The contribution of defects in the normal transmission of hormone-dependent signals to the development of endocrine cancers has been widely analyzed and the knowledge derived from these studies has allowed us to develop many successful therapeutic strategies. However, in many cases these hormonal treatments become ineffective despite the fact that cancer cells maintain normal expression levels of wild-type hormone nuclear receptors. Less is known about the involvement of altered Notch signaling in the origin and progression of cancer, although there is clear evidence indicating that deregulation of Notch activity occurs in several types of tumors, including highly prevalent hormone-dependent types of cancer such as breast, ovarian and prostate cancer. This review will summarize accumulating data suggesting that Notch signaling plays a key role in the control of proliferation, differentiation and survival of prostate epithelial cells. Notch signals are required for normal prostate development and homeostasis, and abnormalities in Notch signaling may be critical during the development of prostate cancer. We will also discuss the possible oncogenic role for alterations in the crosstalk mechanisms between Notch and androgen-dependent signals during tumorigenesis in the prostate and how they could influence the outcome of anti-cancer hormonal treatments.
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Novel Virally Targeted Therapies of EBV-Associated Tumors
More LessEBV is associated to the development of several malignancies of lymphoid and epithelial origin, including Burkitt's Lymphoma, post-transplant lymphoproliferative disorders, Hodgkin's disease, AIDS-associated lymphomas, NK/T cell lymphoma and Nasopharyngeal carcinoma. EBV genes play an essential role in the development of the malignant phenotype and therefore molecules interfering with the function of these genes may represent an essential tool to treat EBV-associated malignancies. Several strategies to inhibit virus-induced tumorigenesis have been developed including antiviral and antitumor molecules, gene therapy approaches, interference with epigenetic regulatory mechanisms, adoptive and active immunotherapeutic protocols. While gene therapy and epigenetic approaches gave inconsistent results, immunological therapies using ex vivo expanded autologous and allogenic cells specific for EBV have obtained promising results. The major challenge is now to improve the current knowledge on virus replication strategies and on the characteristics of protective immune response that may result in more effective therapeutic protocols.
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Interaction Between Estrogen Receptor Alpha and Insulin/IGF Signaling in Breast Cancer
Estrogens and insulin/Insulin like growth factor 1 (IGF-I) have potent positive effects on the proliferation of mammary epithelial cells and estrogen-dependent breast cancer cells. A cooperative crosstalk between estrogens and insulin/ IGF-I signaling pathways exists and it plays a critical role in breast carcinogenesis, tumor cell proliferation, differentiation and survival through the modulation of multiple biological events. The biological effects of estrogens are mainly mediated by the activation of estrogen receptor (ERα) whose activity is deeply influenced by the insulin/IGF-I signaling pathway. On the other hand, estrogens enhance insulin signaling by increasing the expression and/or the functional activity of some proteins involved in the insulin/IGF-I pathway. This review will focus on the critical node of the IGF-I network involved in the crosstalk with ERα and implicated in breast cancer development and progression.
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Obesity-Enhanced Colon Cancer: Functional Food Compounds and their Mechanisms of Action
Authors: Jairam Vanamala, Christopher C. Tarver and Peter S. MuranoObesity is rapidly becoming a global phenomenon. This is more than a cosmetic issue as obesity is associated with several life-threatening diseases, including colon cancer. Insulin resistance and inflammation, underlying factors in obesity-related diseases, promote colonocyte proliferation and suppress programmed cell death, or apoptosis, by activating the insulin-like growth factor (IGF) and prostaglandin pathways. These pathways converge on the Wnt pathway, which is implicated in colon carcinogenesis. Despite tremendous advances in our understanding of the molecular mechanisms involved in colon carcinogenesis, mortality due to colon cancer world-wide is unacceptably high. Even though conventional therapies can prolong a patient's life-span a few years, they cause serious side effects. Thus, there is growing interest in functional foods and dietary bioactive compounds with chemopreventive properties. This search is fueled by the epidemiological studies indicating that plant-based diets are protective against several types of cancers. This review provides a brief summary of the IGF and prostaglandin pathways, which are implicated in obesity-enhanced colon cancer, and some of the functional foods/dietary compounds that target these pathways. It is essential to understand the molecular mechanisms involved in chemoprevention before providing appropriate science-based dietary recommendations to prevent colon cancer in both obese and non-obese individuals.
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Luteolin, a Flavonoid with Potential for Cancer Prevention and Therapy
Authors: Yong Lin, Ranxin Shi, Xia Wang and Han-Ming ShenLuteolin, 3',4',5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, luteolin sensitizes cancer cells to therapeuticinduced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3'-kinase (PI3K)/Akt, nuclear factor kappa B (NF-κB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to luteolin. In this review, we summarize the progress of recent research on luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of luteolin.
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Volumes & issues
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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Volume 1 (2001)