Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 13, Number 7, 2007

Contents


Targeting the IGF-I Receptor Signaling Pathway: Implications for Human Cancer Therapy
Executive Editors: A. Ciampolillo and F. Giorgino


Editorial Pp. 661-662


The IGF-I Signaling Pathway Pp. 663-669
L. Laviola, A. Natalicchio and F. Giorgino
[Abstract]


The Role of Insulin Receptor Isoforms and Hybrid Insulin/IGF-I Receptors in Human Cancer Pp. 671-686
A. Belfiore
[Abstract]


Anti-Apoptotic Actions of Insulin-Like Growth Factors: Lessons from Development and Implications in Neoplastic Cell Transformation Pp. 687-703
I. Varela-Nieto, M. Hartl, I. Gorospe and Y. León
[Abstract]


Crosstalk Between IGF Signaling and Steroid Hormone Receptors in Breast Cancer Pp. 705-717
D. Sisci and E. Surmacz
[Abstract]


The IGF Axis in Prostate Cancer Pp. 719-727
S. Monti, L. Proietti-Pannunzi, A. Sciarra, F. Lolli, P. Falasca, M. Poggi and V. Toscano
[Abstract]


The IGF-I Axis in Thyroid Carcinoma Pp. 729-735
A. Ciampolillo, C. De Tullio, E. Perlino and E. Maiorano
[Abstract]


Anti-Tumor Activity of Non-Nucleosidic Reverse Transcriptase Inhibitors Pp. 737-742
M. Landriscina, C. Spadafora, M. Cignarelli and C. Barone
[Abstract]


General Articles


Pancreatic Islets Under Attack: Cellular and Molecular Effectors Pp. 749-760
M. Pearl-Yafe, A. Kaminitz, E.S. Yolcu, I. Yaniv, J. Stein and N. Askenasy
[Abstract]


Drug Carriers in Pharmaceutical Design: Promises and Progress Pp. 761-769
R.C. Dutta
[Abstract]




Abstracts


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Editorial: Targeting the IGF-I Receptor Signaling Pathway: Implications for Human Cancer Therapy

A common molecular abnormality in human cancer is the presence of multiple autocrine loops, with one of the most prominent involving co-expression of insulin-like growth factor-I (IGF-I) and its receptor. Epidemiological studies have shown that increased serum levels of IGF-I and decreased levels of its predominant binding protein, IGFBP-3, correlate with an increased risk for several types of cancers. IGF-I has also been shown to be an important regulator of VEGF expression and angiogenesis in several cancers. In writing this review issue, we have sought to provide an updated overview on the role of IGFs and the IGF-I receptor signaling pathway in human cancer.

The first article by Laviola et al. [1] provides a general overview on IGF-I receptor structure and function, its intracellular signaling pathways, and some important implications deriving from the activation of the IGF-I signal transduction system in specific tissues (e.g., skeletal muscle, heart, brain, beta-cells). In particular, novel actions resulting from activation of the PI 3-kinase/Akt cascade by the IGFs are illustrated, including promotion of survival of cardiac myocytes both in vitro and in vivo, protection of cells from reperfusion injury in vivo, and preservation of myocardial function. Moreover, the effects of IGF-I on the neuronal tissue are described with particular emphasis on IGF-I regulation of brain development, neuronal survival, and synaptogenesis during early postnatal life. Finally, the role of the IGF system in the beta-cells is also described, including the modulatory effects on insulin secretion and the regulation of early islet development and hypertrophic response to insulin resistance or pancreatic injury.

The article by Belfiore [2] focuses on the emerging role of the IGF-I receptor homolog receptor, the insulin receptor (IR), in cancer. In fact, several epidemiological studies have shown that insulin resistance states are characterized by hyperinsulinemia, and are associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon, and kidney. IR is overexpressed in several human malignancies, and this occurs by multiple mechanisms. Interestingly, one of the two IR isoform (IR-A) is specifically overexpressed in cancer cells. IR-A is the fetal isoform of the IR and has the peculiar characteristic to bind and to be activated not only by insulin but also by IGF-II. Overexpression of the IR-A has thus emerged as a major mechanism of IGF system overactivation in cancer. These findings may have important implications for both the prevention and treatment of the most frequent forms of cancer.

Varela-Nieto et al. [3] discuss the mechanisms of IGF-I survival actions in development. The developing inner ear is taken as a model system to study the anti-apoptotic actions of the IGF system. The inner ear is a complex sensory organ responsible for equilibrium and sound detection in vertebrates. IGF-I is expressed during the early embryonic development in the otic vesicle and in neuroblasts destined to generate the auditory ganglia. Interference of endogenous IGF-I activity impairs survival, proliferation, and differentiation of the otic neuroblasts, suggesting that survival promotion is the main activity of this factor. Moreover, the biological activities of ectopic IGF-I are described in avian cell systems. The mitogenic and anti-apoptotic functions of IGF-I become apparent upon ectopic expression in primary avian fibroblasts in which this growth hormone enhances cell proliferation and allows cells to escape from apoptosis induced by low serum concentrations. These experiments have suggested that IGF-I cannot be regarded as a typical oncoprotein but rather as a growth factor inducing mitogenesis and ensuring cell survival in stress situations, and as a tumor promoter in cells with aberrant IGF signaling.

The review article by Scisci and Surmacz [4] focuses on the crosstalk between the IGF system and several steroid hormones (e.g., estrogens, progestins and androgens) implicated in the pathogenesis of breast cancer. The biological effects of steroid hormones are mediated by their cognate receptors, which are members of the nuclear receptors superfamily of transcriptional activators. Steroid hormone receptors, in addition to being induced by their own ligands, are also regulated by cellular kinases activated by growth factors. Breast cancer is thought to be related to aberrant activation of steroid receptors and up-regulation of growth factor signalling pathways, such as the IGF-I pathway. IGF-I can enhance steroid receptor-mediated transcription by inducing phosphorylation of various proteins involved in this process as well as by influencing steroid receptor turnover. On the other hand, steroids can modulate the expression and function of different protein components of the IGF-I system. Direct interaction between steroid receptors and IGF-I receptors or its signalling molecules modify the response to both steroid hormones and IGFs.

Toscano et al. [5] analyze the epidemiological data, obtained both in vitro and in vivo, implicating the IGF axis in prostate cancer development. The IGF axis plays a pivotal role in the development, growth and progression of prostate cancer by acting through endocrine, paracrine and autocrine mechanisms. IGF-I is the main player of the endocrine action. Indeed, both prostate cancer cell lines and epithelial and stromal cells within the normal prostate express IGF-I receptors and respond to the mitogenic and anti-apoptotic activities of IGF-I. In addition, circulating IGF-I levels, modulated by IGFBP-3, have been found to be elevated many years before the diagnosis of prostate cancer, supporting the hypothesis that IGF-I may be an aetiological factor in this disease. Even though further studies are necessary to clarify the involvement of the different components of the IGF system in prostate carcinogenesis, the IGF axis seems to represents a likely target for chemoprevention and therapeutic intervention in prostate cancer patients.

Ciampolillo et al. [6] analyze the IGF-I system in thyroid tumors. In human thyroid carcinomas, an increased immunoreactivity of both IGF-I and the IGF-I receptor has been demonstrated, and this was found to be associated with up-regulation of the IGF-I mRNA. Overexpression and overactivation of Akt have also been reported in a subset of human thyroid cancers, and this phenomenon seems to be involved in the progression of tumor growth as well as in preventing apoptosis. Moreover, differentiated thyroid carcinomas strongly express VEGF in larger amounts than normal thyroid tissue, and IGF-I stimulates VEGF expression in a PI 3-kinase-dependent manner, via activation of the transcription factors AP-1 and HIF-1. The inhibition of thyroid cancer growth in vivo can be obtained by blocking the VEGF receptor with anti-VEGF monoclonal antibodies, thus supporting the role of VEGF as regulator of thyroid tumor progression. A better understanding of the biological mechanisms responsible for the uncontrolled growth of hormonally regulated cancers is critical to devise novel effective diagnostic and/or prognostic approaches which can be potentially used to predict the progression of the disease in its different clinical phases.

Lastly, the article by Landriscina et al. [7] examines the possibility that some aggressive types of neoplasms can be treated by using a novel class of anti-cancer therapeutic drugs, i.e. the reverse transcriptase (RT) inhibitors. These molecules exert powerful cytostatic and differentiating activities in several models of human cancers both in vitro and in vivo, and this is associated with inhibition of endogenous RT activity. Based on preclinical observations, the Authors also discuss the working hypothesis that the differentiating activity of RT inhibitors may re-establish or improve the efficacy of conventional treatments under specific conditions. For example, exposure of thyroid anaplastic tumor cells to efavirenz or nevirapine, two RT inhibitors, induces significant morphological signs of cell differentiation such as increases in cell adhesion, re-establishment of monolayer cell growth, and reductions in cluster formation. This is associated with restored response to radioiodine. These results strongly reinforce the hypothesis that RT can be regarded as a novel molecular target in cancer therapy, and that RT inhibitors may be effective as differentiating compounds able to restore sensitivity to conventional therapies.

References
[1] Laviola L, Natalicchio A, Giorgino F. The IGF-I signaling pathway. Curr Pharm Des 2007; 13(7): 663-669.

[2] Belfiore A. The role of insulin receptor isoform and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 2007; 13(7): 671-686.

[3] Varela-Nieto I, Hartl M, Gorospe I, Leon Y. Anti-apoptotic actions of insulin-like growth factors: lessons from development and implications in neoplastic cell transformation. Curr Pharm Des 2007; 13(7): 687-703.

[4] Sisci D, Surmacz E. Crosstalk between IGF signaling and steroid hormone receptors in breast cancer. Curr Pharm Des 2007; 13(7): 705-717.

[5] Monti S, Proietti-Pannunzi L, Sciarra A, Lolli F, Falasco P, Poggi M, Toscano V. The IGF axis in prostate cancer. Curr Pharm Des 2007; 13(7): 719-727.

[6] Ciampolillo A, De Tullio C, Perlino E, Maiorano E. The IGF-I axis in thyroid carcinoma. Curr Pharm Des 2007; 13(7): 729-735.

[7] Landriscina M, Spadafora C, Cignarelli M, Barone C. Anti-tumor activity of non-nucleosidic reverse transcriptase inhibitors. Curr Pharm Des 2007; 13(7): 737-747.


Francesco Giorgino
Professor of Endocrinology
University of Bari, Bari
Italy

Anna Ciampolillo
Assistant Professor of Endocrinology
University of Bari, Bari
Italy


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The IGF-I Signaling Pathway
L. Laviola, A. Natalicchio and F. Giorgino

The insulin-like growth factor (IGF)-I is implicated in the regulation of protein turnover and exerts potent mitogenic and differentiating effects on most cell types. IGF-I biological actions are mediated by the IGF-I receptor, comprised of two extra-cellular α-subunits, containing hormone binding sites, and two membrane-spanning β-subunits, encoding an intracellular tyrosine kinase. Hormone binding activates the receptor kinase, leading to receptor autophosphorylation and tyrosine phosphorylation of multiple substrates, including the IRS and Shc proteins. Through these initial tyrosine phosphorylation reactions, IGF-I signals are transduced to a complex network of intracellular lipid and serine/threonine kinases that are ultimately responsible for cell proliferation, modulation of tissue differentiation, and protection from apoptosis. This review will focus on the IGF-I receptor structure and function, its intracellular signaling pathways, and some important implications of the activation of the IGF-I signal transduction system in specific tissues.


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The Role of Insulin Receptor Isoforms and Hybrid Insulin/IGF-I Receptors in Human Cancer
A. Belfiore

This review will focus on the emerging role of the insulin receptor (IR) in cancer. Several epidemiological studies have shown that insulin resistance states, characterized by hyperinsulinemia, are associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon and kidney. Recent data have elucidated some molecular mechanisms by which IR is involved in cancer. First, IR is overexpressed in several human malignancies. Interestingly, one of the two IR isoform (IR-A) is especially overexpressed in cancer. IR-A is the IR fetal isoform and has the peculiar characteristic to bind not only insulin but also IGF-II. Second, IR forms hybrid receptors with the homologous IGF-IR, which is also commonly overexpressed in cancer. These hybrid receptors containing IR-A hemidimers have broad binding specificity as they bind IGF-I and also IGF-II and insulin. By binding to hybrid receptors, insulin may stimulate specific IGF-IR signaling pathways. Overexpression of IR-A is, therefore, a major mechanism of IGF system overactivation in cancer.

These findings may have important implications for both the prevention and treatment of common human malignancies. They underline the concept that hyperinsulinemia, associated with insulin resistance and obesity, should be treated by changes in life style and/or pharmachological approaches to avoid an increased risk for cancer. IR-A isoform and hybrid receptors should be regarded, therefore, as potential molecular targets for novel anti-cancer therapies.


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Anti-Apoptotic Actions of Insulin-Like Growth Factors: Lessons from Development and Implications in Neoplastic Cell Transformation
I. Varela-Nieto, M. Hartl, I. Gorospe and Y. León

Insulin-like growth factor-I (IGF-I) is widely expressed during development, and is actively involved in the regulation of cell growth, proliferation, and differentiation. Underlying these activities is the capacity of IGF-I to promote survival in a variety of cell types, including those of the nervous system. However, in adult tissues deregulation of the IGF system can cause undesired cell survival and therefore excessive cell proliferation. Here, we review the contribution of IGF-I in developmental processes with a focus on the development of the inner ear, as well as pathological implications resulting from IGF-I deregulation during cancer.


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Crosstalk Between IGF Signaling and Steroid Hormone Receptors in Breast Cancer
D. Sisci and E. Surmacz

Breast cancer development and progression is regulated by crosstalk between steroid hormones (SHs) (e.g., estrogens, progestins and androgens) and growth factors such as insulin-like growth factors (IGFs), insulin, epidermal growth factors (EGFs), transforming growth factors, and vascular endothelial growth factor. The biological effects of SHs are mediated by the nuclear receptors acting as transcriptional activators. Steroid hormone receptors (SRs), in addition to being induced by their own ligands, are also regulated by cellular kinases activated by growth factors. Growth factors are known to influence the expression and activity of SRs as well as regulate the action of various SR transcriptional co-factors. In turn, the expression of growth factor receptors, their ligands, and signaling molecules is often controlled by SHs. This review will focus on crosstalk between the IGF-I system and several SRs implicated in breast cancer.


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The IGF Axis in Prostate Cancer
S. Monti, L. Proietti-Pannunzi, A. Sciarra, F. Lolli, P. Falasca, M. Poggi and V. Toscano

Prostate cancer, the most frequent non-cutaneous malignancy in men from industrialized countries, is a growing medical problem, representing the second leading cause of male cancer deaths. In the last decade, converging evidence from epidemiological and biological studies suggests that the Insulin-like Growth Factor (IGF) axis is involved in the tumorigenesis and neoplastic growth of prostate cancer. Epidemiological observations indicated that circulating IGF-I levels are positively associated with the increased risk of prostate cancer. The activation of type I IGF receptor (IGF-IR) by IGF-I and/or IGF-II, has mitogenic and antiapoptotic effects on normal and malignant prostate cells. Altered expression of IGF axis components has also been reported in vitro and in animal models of prostate cancer, as well as in human prostate cancer tissue samples. In this review we address and analyze epidemiological studies, in vitro and in vivo cancer models, and human ex vivo prostate cancer researches performed to date supporting the role of IGF axis in prostate cancer.


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The IGF-I Axis in Thyroid Carcinoma
A. Ciampolillo, C. De Tullio, E. Perlino and E. Maiorano

Insulin like-growth factor I (IGF-I) has been involved in the pathogenesis of a variety of human neoplasia due to the mitogenic and anti-apoptotic properties of its cognate receptor. In human thyroid carcinomas, we have previously documented an increased immunoreactivity of both IGF-I and the IGF-I receptor (IGF-I R) associated with up regulation of IGF-I mRNA . Immunoreactivity of IGF-I and cognate receptor positively correlated with tumor diameter and wide intrathyroidal extension but not with patient’s gender and age or with the stage of the tumors and the occurrence of limph node metastases.

Most experimental studies indicate that the effects of IGF-I on target cells are regulated in a complex fashion and depend on the simultaneous occurrence of IGF-IR and the binding proteins.


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Anti-Tumor Activity of Non-Nucleosidic Reverse Transcriptase Inhibitors
M. Landriscina, C. Spadafora, M. Cignarelli and C. Barone

Reverse Transcriptase (RT) activity is historically associated with the replication of infectious retroviruses. Cellular RT-coding genes have subsequently been identified in eukaryotic genomes. These genes are harbored within retrotransposable elements (retrotransposons and endogenous retroviruses), mobile DNA sequences characterized by the ability to integrate in mammalian genomes through RNA intermediates. Retrotransposition is mediated by an RT activity that catalyzes the reverse transcription of RNA into cDNA copies. A vast body of correlative evidence links up-regulated RT activity to cell systems with a high proliferative potential and low differentiation level, including embryonic tissues and tumors. In contrast, RT is silenced, or expressed at low levels, in differentiated cells. In recent work, we have used non-nucleosidic RT inhibitors widely employed to treat HIV infection and we have observed that these molecules exert a powerful cytostatic and differentiating activity in several models of human cancers both in vitro and in vivo, associated with the inhibition of endogenous RT activity. This review addresses the potential role of RT inhibitors as new anticancer therapeutic drugs. Based on preclinical observations, we also discuss the working hypothesis that the differentiating activity of RT inhibitors may re-establish or improve the efficacy of conventional treatments in specific conditions, such as hormone-refractory prostate carcinoma, anaplastic thyroid tumors and hematological malignancies. These novel findings strongly support the need for clinical trials to test the anti-tumor activity of RT inhibitors in specific malignancies.


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Pancreatic Islets Under Attack: Cellular and Molecular Effectors
M. Pearl-Yafe, A. Kaminitz, E.S. Yolcu, I. Yaniv, J. Stein and N. Askenasy

Abundant information is available on the involvement of various cellular and molecular mechanisms in β cell apoptosis. The experimental evidence is controversial and difficult to reconcile, and the mechanisms of evasion of the autoreactive clones from immune surveillance are poorly understood. Multiple apoptotic pathways play a role in destructive insulitis, including perforin/granzyme, Fas/Fas-ligand (FasL), and other members of the necrosis factor superfamily. These pathways present redundant behaviors in both the initial and late stages of β cell injury, and at the same time, each molecular mechanism is dispensable in the evolution of autoimmune diabetes. There may be a preferential use of perforin/granzyme in CD8⁺ T cell-mediated lysis, which participates in onset of autoimmunity, and a predominance of FasL in CD4⁺ T cell-mediated insulitis. Several cytokines released in the inflammatory infiltrate induce Fas expression in β cells, priming them to FasL-mediated apoptosis. In this review, we focus on the possible participation of multiple cell subsets and molecular mechanisms in the pathogenesis of diabetes to the point where inflammation incites an irreversible vicious cycle that perpetuates β cell death.


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Drug Carriers in Pharmaceutical Design: Promises and Progress
R.C. Dutta

Ever since pure molecular entities have been adapted as drug, varied manifestations other than elimination of infections are frequently been acknowledged as side effects. Contemporary drug research focuses on these issues besides developing new molecules for the restoration of unnatural functional deviations in various tissues and organs. The most promising advancement to achieve this concept of ideal drug is the encapsulation of drug in biocompatible nano or microspheres. Encapsulation can insulate the toxic drugs and lease a better half life to molecules undergoing spontaneous degradation under physiological conditions. It is also worthwhile to incorporate along some immunomodulators to strengthen and channelize the innate immune response of the host in right direction. This holistic approach would also prevent the physiological modulations dictated by invading pathogens, which paralyze the important functionaries of the host. Lipoproteins, lipid like molecules and probiotic non-colonizing bacterial membrane mimics might prove to be the best ingredients for encapsulation. Some synthetic non-immunogenic supra molecules like fullarenes and dendrimers also exhibit great potential for the development of new encapsulation technology. Here an attempt is made to review the progress in terms of aims and achievements in the area of drug carriers and encapsulation with its overall impact on therapeutic industry.