Page: 3-21 (19)
Author: Sarah Croessmann, Justin Cidado, John P. Gustin, David Cosgrove and Ben Ho Park
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The development of targeted therapies with true specificity for cancer relies upon exploiting differences between cancerous and normal cells. Genetic and genomic alterations including somatic mutations, translocations, and amplifications have served as recent examples of how such differences can be exploited as effective drug targets. Small molecule inhibitors and monoclonal antibodies directed against the protein products of these genetic anomalies have led to cancer therapies with high specificity and relatively low toxicity. Our group and others have demonstrated that somatic mutations in the PIK3CA gene occur at high frequency in breast and other cancers. Moreover, the majority of mutations occur at three hotspots, making these ideal targets for therapeutic development. Here we review the literature on PIK3CA mutations in cancer, as well as existing data on p110α inhibitors and inhibitors of downstream effectors for potential use as targeted cancer therapeutics.
Page: 22-50 (29)
Author: Bing-Hua Jiang and Ling-Zhi Liu
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AKT is a central signaling molecule in regulating cell survival, proliferation, tumor growth and angiogenesis. Upstream components of AKT signaling pathway such as PI3K, PTEN, and Ras are commonly mutated in many human cancers. Some miRNAs are also involved in regulating PI3K/AKT signaling pathway. Recently it is found that AKT plays an important role in regulating normal vascularization and pathological angiogenesis. Angiogenesis is required for tumor growth and metastasis when tumor reaches more than 1 mm in diameter. This review focuses on the role and potential mechanism of AKT signaling in regulating angiogenesis. Recent studies have shown that AKT activation is necessary and sufficient to regulate VEGF and HIF-1α expression in human cancer cells. VEGF and HIF-1α are potent inducers of angiogenesis. It was found that AKT activation induces VEGF and HIF-1α expression through its two downstream molecules HDM2 and p70S6K1. On the other hand, AKT transmits the upstream signals from growth factors, cytokines, heavy metals, and oncogenes for regulating VEGF and HIF-1α expression in human cancer cells. AKT activation and VEGF expression can be inhibited by different natural products used for cancer prevention. Thus, inhibition of AKT and its downstream targets offers a new approach for targeting angiogenesis, which could be important for the development of new cancer therapeutics in the future.
Page: 51-119 (69)
Author: P. Sapra Sharma and R. Sharma
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Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases, which regulate multiple pathways such as the cell division cycle, apoptosis, transcription, and neuronal functions. Their sequential activation ensures the correct timing and ordering of events required for cell cycle progression. Uncontrolled proliferation is a hallmark of cancer cells. Over the past two decades, it has become increasingly clear that in many human cancers, hyperactivity of CDKs is one of the mechanisms underlying the physiological hyper-proliferation. Therefore, inhibition of CDKs, through the insertion of small molecules into its ATP binding pocket has emerged as a potential therapy method for cancers. For these reasons an intensive search for pharmacological inhibitors of these protein kinases has been carried out during the last decade. Consequently, a number of small molecules with CDK inhibitory properties have been developed. Many of these have been evaluated as potent inhibitors and some are currently in clinical-trials for various types of cancer. This review reports various CDK inhibitors, natural as well as small molecules, along with their reported activities for various CDKs. It will highlight the potential for the development of novel anti-cancer molecules.
Cellular FLICE-Like Inhibitory Protein (c-FLIP): A Key Anti- Apoptotic Factor and a Target for Cancer Therapy
Page: 120-145 (26)
Author: Ahmad R. Safa
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Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of apoptosis. c-FLIP impedes tumor necrosis factor-α (TNF-α), Fas-L, TNF-related apoptosis-inducing ligand (TRAIL), and chemotherapy-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIPL) and short (c-FLIPS) splice variants in human cells. Accumulating evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIPL in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, several chemotherapeutic agents induce c-FLIP downregulation in neoplastic cells. Moreover, numerous small molecule inhibitors have been found which cause degradation of c-FLIP variants and decrease mRNA and protein levels of c-FLIPL and c-FLIPS. In this chapter, I assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.
Pin1: A Promising Novel Diagnostic and Therapeutic Target that Acts on Numerous Cancer-Driving Pathways
Page: 146-171 (26)
Author: Greg Finn, Man-Li Luo, Xiao Zhen Zhou and Kun Ping Lu
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Proline-directed phosphorylation is a common and central regulatory mechanism in cell proliferation and oncogenic transformation. In fact, numerous oncogenes and tumor suppressors themselves are directly regulated by proline-directed phosphorylation and/or can trigger signaling pathways involving proline-directed phosphorylation. Our recent identification of the phosphorylation dependent prolyl isomerase Pin1 has uncovered a novel signaling mechanism controlling protein function after phosphorylation via conformational changes. Importantly, Pin1 deregulation plays a pivotal role in the development of some diseases, providing a new therapeutic option, most notably for cancers. Pin1 is prevalently overexpressed and its levels correlate with poor clinical outcome in human cancers. Significantly, Pin1 is required for activation of multiple oncogenic pathways by acting on numeroous oncogenes and tumor suppressors. Moreover, Pin1 knockdown or knockout inhibits cancer cell growth and prevents cell transformation and tumorigenesis induced either by oncogenes or tumor suppressors in vitro and in vivo. Pin1-mediated post-phosphorylation isomerisation represents a unique regulatory mechanism in cell signalling whose upregulation during tumorigenesis promotes the pro-proliferative capacity of tumour cells. Accumulating evidences indicate that Pin1 may represent a novel tumour marker and potential therapeutic target. Therefore, there is an urgent need to develop Pin1-specific inhibitors because they may have the desired property to suppress numerous oncogenic pathways, which are often activated simultaneously in cancers, especially in those aggressive and drug-resistant ones.
Anticancer Immunotherapy in Combination with Proapoptotic Therapy - Possible Therapeutic Strategies for Enhancement of Anticancer Immune Reactivity in Autologous Immunocompetent Cells and After Allogeneic Stem Cell Transplantation
Page: 172-206 (35)
Author: Håkon Reikvam, Elisabeth Ersvær, Guro Kristin Melve, Astrid Olsnes Kittang, Bjørn Tore Gjertsen and Øystein Bruserud
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Induction of immune responses against cancer-associated antigens is possible, but the optimal use of this strategy remains to be established and especially the combination of T cell therapy and new targeted therapeutic agents should be investigated. The design of future clinical studies has to consider several issues. Firstly, induction of anticancer T cell reactivity seems most effective in patients with low disease burden. Initial disease-reducing therapy including surgery, irradiation and conventional or new targeted chemotherapy should therefore be used, preferably through induction of immunogenic cancer cell death. Secondly, after the induction phase effector T cells will induce cancer cell apoptosis mainly through the intrinsic apoptosis-regulating pathway. The effect of this effector T cell function should be strengthened by administration of chemotherapy that mediates additional proapoptotic signalling through the external apoptosis-regulating pathway, inhibition of survival signalling or blocking of anti-apoptotic signalling. Thirdly, the status of the immune system has to be considered, including the postchemotherapy CD4+ T cell defect, the balance between proinflammatory and immunosuppressive T cell subsets (e.g. regulatory T cells versus Th17 cells), and immunoregulatory mesenchymal cells that can be detected within tumors. Immunotherapy should probably be initiated early after disease-reducing therapy when the cancer cell burden is lowest and a focus should then be to alter the balance in favour of proinflammatory T cell subsets. All these issues need to be considered in the design of future clinical studies combining chemotherapy and immunotherapy.
Page: 207-237 (31)
Author: Samuel Cos, Alicia González, Virginia Alvarez-García, Carolina Alonso-González and Carlos Martínez-Campa
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Melatonin exerts oncostatic effects on different kinds of tumors, especially on hormone-dependent breast cancer. The general conclusion is that melatonin, in vivo, reduces the incidence and growth of chemically-induced mammary tumors in rodents, and, in vitro, inhibits the proliferation and invasiveness of human breast cancer cells. Both studies support the hypothesis that melatonin inhibits the growth of breast cancer by interacting with estrogen-signaling pathways through three different mechanisms: (a) indirect neuroendocrine effect which includes the melatonin down-regulation of the hypothalamic-pituitary-reproductive axis and the consequent reduction of circulating levels of gonadal estrogens, (b) direct melatonin actions at tumor cell level by interacting with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator (SERM), and (c) the regulation of the enzymes involved in the biosynthesis of estrogens in peripheral tissues, thus behaving as a selective estrogen enzyme modulator (SEEM). As melatonin reduces the activity and expression of aromatase, sulfatase and 17β-hydroxysteroid dehydrogenase and increases the activity and expression of estrogen sulfotransferase, it may protect mammary tissue from excessive estrogenic effects. Thus, a single molecule has both SERM and SEEM properties, one of the main objectives desired for the breast antitumoral drugs. Since the inhibition of enzymes involved in the biosynthesis of estrogens is currently one of the first therapeutic strategies used against the growth of breast cancer, melatonin modulation of different enzymes involved in the synthesis of steroid hormones make, collectively, this indolamine an interesting anticancer drug in the prevention and treatment of estrogen-dependent mammary tumors.
Page: 238-263 (26)
Author: V. Rodriguez-Menendez, L. Tremolizzo and G. Cavaletti
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Histone deacetylase inhibitors (HDACi) belong to a novel class of drugs able to act on the epigenome, indirectly remodeling the spatial conformation of the chromatin: by increasing histone acetylation these drugs ultimately promote the detachment of DNA from the nucleosome octamer, thereby allowing transcription factors access to the double helix. Such a mechanism of action is of particular interest in the field of cancer treatment, as the reactivation of silenced tumor suppressor genes may be considered as being an important target at which to aim; indeed, it is currently believed that dysregulation of the epigenome plays a major role in cancer. Interestingly, some of the compounds belonging to the HDACi family have additional therapeutic properties, as in the case of valproate that may ameliorate neuropathic pain in animal models and in patients. Conceivably, this is a noteworthy observation, since peripheral neuropathy is a potentially severe side effect of several classes of anticancer agents, such as platinum-derived drugs, antitubulins or protesome inhibitors, limiting effective treatment of the underlying cancer. Based on these data, in this review we will argue that, with respect to other anticancer agents available nowadays, HDACi might offer the advantage not only of targeting the neoplastic disorder, but also of preventing peripheral neuropathies, possibly displaying a complementary mechanism of action.
Advances in Cancer Drug Targets is an e-book series that brings together recent expert reviews published on the subject with a focus on strategies for synthesizing and isolating organic compounds and elucidating the structure and nature of DNA. The reference work serves to give readers a brief yet comprehensive glance at current theory and practice behind employing chemical compounds for tackling tumor suppression, DNA site specific drug targeting and the inhibition of enzymes involved in growth control pathways. The reviews presented in this series are written by experts in pharmaceutical sciences and molecular biology. These reviews have been carefully selected to present development of new approaches to anti-cancer therapy and anti-cancer drug development. This e-book volume will be of special interest to molecular biologists and pharmaceutical scientists.