Current Cancer Drug Targets

ISSN: 1568-0096

Current Cancer Drug Targets
Volume 8, Number 1, February 2008

Contents

Akt Pathway in Oncogenesis and as a Target for Anti-Cancer Therapy
Guest Editor: Jin Q. Cheng


Editorial Pp. 1


Advances of AKT Pathway in Human Oncogenesis and as a Target for Anti-Cancer Drug Discovery Pp. 2-6
George Z. Cheng, Sungman Park, Shaokun Shu, Lili He, William Kong, Weizhou Zhang, Zengqiang Yuan, Lu-Hai Wang and Jin Q. Cheng
[Abstract]


The PI3K/Akt Pathway: Recent Progress in the Development of ATP-Competitive and Allosteric Akt Kinase Inhibitors Pp. 7-18
Craig W. Lindsley, Stanley F. Barnett, Mark E. Layton and Mark T. Bilodeau
[Abstract]


AKT Signaling in Regulating Angiogenesis Pp.19-26
Bing-Hua Jiang and Ling-Zhi Liu
[Abstract]


Deregulation of the Akt Pathway in Human Cancer Pp. 27-36
Eriko Tokunaga, Eiji Oki, Akinori Egashira, Noriaki Sadanaga, Masaru Morita, Yoshihiro Kakeji and Yoshihiko Maehara
[Abstract]


General Articles


Cellular FLICE-Like Inhibitory Protein (C-FLIP): A Novel Target for Cancer Therapy Pp. 37-46
Ahmad R. Safa, Travis W. Day and Ching-Huang Wu
[Abstract]


Targeting P-glycoprotein for Effective Oral Anti-Cancer Chemotherapeutics Pp. 47-52
M. Bebawy and D.M. Sze
[Abstract]


Inhibitors of Cyclin Dependent Kinases: Useful Targets for Cancer Treatment Pp. 53-75
P. Sapra Sharma, R. Sharma and R. Tyagi
[Abstract]


Small Molecule Tyrosine Kinase Inhibitors: Potential Rol in Pediatric Malignant Solid Tumors Pp. 76-85
Jochen Rössler, Birgit Geoerger, Melissa Taylor and Gilles Vassal
[Abstract]




Abstracts


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Editorial:

The first evidence that AKT plays a role in carcinogenesis was provided by the isolation of the transforming retrovirus from an AKR mouse T-cell lymphoma about thirty years ago [1], which was subsequently shown to contain transduced sequences of cellular origin. In early 1990, the intact viral oncogene, v-akt, was cloned [2]. The predicted oncoprotein encoded by v-akt harbored viral Gag sequences fused to a kinase related to protein kinase C. The tumorigenic potential of the v-akt product was found to come about because of the presence of a myristylation site at its amino-terminus, with resultant translocation to the plasma membrane and constitutive kinase activity [3]. AKT is now known to have a family of three closely related cellular homologues, named AKT1, AKT2 and AKT3. All three AKT members are activated by phosphatidylinositol 3-kinase (PI3K) and inhibited by tumor suppressor PTEN [4].

Accumulated evidence indicates that AKT is a major signaling pathway that regulates cell proliferation and survival, cell growth (size), glucose metabolism, cell motility and angiogenesis [4]. Alterations of this pathway account for approximately half of various types of human malignancy. Thus, AKT presents an exciting target for molecular therapeutics. This issue of Curr Cancer Drug Targets Reviews includes perspectives on AKT normal cellular functions and biological consequences of alterations of this pathway, as well as small molecule inhibitors of AKT. Three reviews focus on AKT regulation of cellular processes and alterations of AKT in human malignancy, one of which highlights the role of major AKT substrates involved in cellular proliferation, survival, transcription and translation [5] and the other two address the role of AKT in angiogenesis [6] and deregulation of the AKT pathway in human cancer [7]. An additional article discusses current approaches to identifying selective inhibitors of the AKT [8].

[1] Staal, S. P.; Hartley, J. W.; Rowe, W. P. Effect of interferon on murine leukemia virus infection. II. Synthesis of viral components in exogenous infection. Proc. Natl. Acad. Sci. USA 1977, 74, 3065-3067.

[2] Bellacosa, A.; Testa, J. R.; Staal, S. P.; Tsichlis, P. N. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 1991, 254, 274-277.

[3] Ahmed, N. N.; Franke, T. F.; Bellacosa, A.; Datta, K.; Gonzalez-Portal, M. E.; Taguchi, T.; Testa, J. R.; Tsichlis, P. N. The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 1993, 8, 1957-1963.

[4] Manning, B. D.; Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 2007, 129, 1261-1274.

[5] Cheng, G. Z.; Park, S.; Shu, S.; He, L.; Kong, W.; Zhang, W.; Yuan, Z. Q.; Wang, L. -H.; Cheng, J. Q. Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr. Cancer Drug Targets 2008, 8(1), 2-6.

[6] Jiang, B. H.; Liu, L. Z. AKT signaling in regulating angiogenesis. Curr. Cancer Drug Targets 2008, 8(1), 19-26.

[7] Tokunaga, E.; Oki, E.; Egashira, A.; Sadanaga, N.; Morita, M.; Kakeji, Y.; Maehara, Y. Deregulation of the Akt pathway in human cancer. Curr. Cancer Drug Targets 2008, 8(1), 27-36.

[8] Lindsley, C. W.; Barnett, S. F.; Layton, M. E.; Bilodeau, M. T. The PI3K/Akt pathway: Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Curr. Cancer Drug Targets 2008, 8(1), 7-18.


Jin Q. Cheng
Molecular Oncology Program
H. Lee Moffitt Cancer Center and Research Institute
Tampa, FL
USA
Tel: 813 745 6915
Fax: 813 745 3829
E-mail: jin.cheng@moffitt.org


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Advances of AKT Pathway in Human Oncogenesis and as a Target for Anti-Cancer Drug Discovery
George Z. Cheng, Sungman Park, Shaokun Shu, Lili He, William Kong, Weizhou Zhang, Zengqiang Yuan, Lu-Hai Wang and Jin Q. Cheng

AKT (also known as PKB) plays a central role in a variety of cellular processes including cell growth, motility and survival in both normal and tumor cells. The AKT pathway is also instrumental in epithelial mesenchymal transitions (EMT) and angiogenesis during tumorigenesis. AKT functions as a cardinal nodal point for transducing extracellular (growth factors including insulin, IGF-1 and EGF ) and intracellular (such as mutated/activated receptor tyrosine kinases, PTEN, Ras and Src) signals. It is positively regulated by phosphatidylinositol 3-kinase and inhibited by phosphatase PTEN. Deregulation of the PI3K/PTEN/AKT pathway is one of the most common altered pathways in human malignancy. In the past few years, significant advances have been made in the understanding of AKT signaling in human oncogenesis and the development of small molecule inhibitor of AKT pathway. Here, we will discuss the regulation and function of AKT as well as targeting AKT for anti-cancer drug discovery.


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The PI3K/Akt Pathway: Recent Progress in the Development of ATP-Competitive and Allosteric Akt Kinase Inhibitors
Craig W. Lindsley, Stanley F. Barnett, Mark E. Layton and Mark T. Bilodeau

This article describes recent advances in the development and biological evaluation of allosteric and ATP-competitive small molecule inhibitors for the serine/threonine kinase Akt (protein kinase B, PKB). Unregulated activation of the PI3K/Akt/PTEN pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers making Akt an exciting new target for cancer therapy. The development of Akt inhibitors has been complicated and hampered by the presence of three Akt isozymes, (Akt1, Akt2 and Akt3) which differ in function and tissue distribution, as well as a lack of Akt specific inhibitors. In the past 18 months, a large number of reports have appeared describing the discovery and development of allosteric Akt kinase inhibitors and classical ATP-competitive Akt kinase inhibitors. This review will discuss the PI3K/Akt/PTEN pathway, allosteric and ATP-competitive Akt kinase inhibitors, their biological evaluation and progress towards target validation.


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AKT Signaling in Regulating Angiogenesis
Bing-Hua Jiang and Ling-Zhi Liu

AKT is a central signaling molecule in regulating cell survival, proliferation, tumor growth and angiogenesis. Upstream com-ponents of AKT signaling pathway such as PI3K, PTEN, and Ras are commonly mutated in many human cancers. 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-1 expression in human cancer cells. VEGF and HIF-1 are potent inducers of angiogenesis. It was found that AKT activation induces VEGF and HIF-1 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-1 expression in human cancer cells. AKT activation and VEGF expression can be inhibited by different natural compounds 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.


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Deregulation of the Akt Pathway in Human Cancer
Eriko Tokunaga, Eiji Oki, Akinori Egashira, Noriaki Sadanaga, Masaru Morita, Yoshihiro Kakeji and Yoshihiko Maehara

Akt (protein kinase B) is a serine/threonine kinase which is a central regulator of widely divergent cellular processes including proliferation, differentiation, migration, survival and metabolism. Akt is activated by a variety of stimuli, through growth factor receptors, in phosphatidylinositol 3-kinase (PI3K)-dependent manner. Akt is also negatively regulated by the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). A disruption of normal Akt/PKB/PTEN signaling frequently occurs in many human cancers, which plays an important role in cancer development, progression and therapeutic resistance. Numerous studies have revealed the blockage of Akt signaling to result in apoptosis and growth inhibition of tumor cells. Therefore, this signaling pathway, including both upstream and downstream of Akt, has recently attracted considerable attention as a new target for effective cancer therapeutic strategies. In fact, many inhibitors of Akt pathway have been identified and clinical studies of some agents are ongoing. In this review, we describe Akt signaling pathway components and its cellular functions as well as the alterations in human cancers and the therapeutic approaches for targeting the Akt pathway in cancer.


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Cellular FLICE-Like Inhibitory Protein (C-FLIP): A Novel Target for Cancer Therapy
Ahmad R. Safa, Travis W. Day and Ching-Huang Wu

Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of death li-gand-induced apoptosis, based on observations that c-FLIP impedes tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-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 and subsequent activation of the caspase cascade. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIP_L) and short (c-FLIP_S) splice variants in human cells. Although c-FLIP has apoptogenic activity in some cell contexts, which is currently attributed to heterodimerization with caspase-8 at the DISC, 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-FLIP_L 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, Taxol, TRAIL, as well as several classes of small molecules induce c-FLIP downregulation in neoplastic cells. Efforts are underway to develop small-molecule drugs that induce c-FLIP downregulation and other c-FLIP-targeted cancer therapies. In this review, we assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.


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Targeting P-glycoprotein for Effective Oral Anti-Cancer Chemotherapeutics
M. Bebawy and D.M. Sze

Oral anticancer drug treatment represents a significant change to current oncology practice. Support for oral anticancer treatment is driven by issues of pharmacoeconomics, accommodating the need for protracted drug administration for many emerging cytostatic therapies, response to patient preference and in improving patient quality of life.

Much focus has concentrated on defining the cellular mechanisms underlying the pharmacokinetic limitations associated with the oral route of administration. However, the potential effects of oral anticancer drugs on gut associated host mediated immunity have been overlooked. Given that the immune system is central for tumour rejection, an assessment of the potential effects oral anticancer drugs may have at this level, and the impact of this on the treatment of gastrointestinal malignancy is of significant clinical importance.

P-glycoprotein is a multidrug transporter that contributes to the reduced bioavailability of many orally administered medications. P-glycoprotein achieves this by virtue of its drug efflux capacity at the level of the gut epithelia. P-glycoprotein is also notorious for contributing to the multidrug resistance phenotype observed in many drug refractory human cancers. Likewise, this drug transporter serves a role in the cells of the immune system; particularly in dendritic cell maturation and function. This multifaceted involvement in drug disposition, cancer drug resistance and regulation of the immune response makes P-glycoprotein an attractive target for the optimization of oral anticancer drug treatment strategies.

This review introduces and discusses for the first time the potential impact that oral anticancer drugs may have on P-glycoprotein expression and function and the potential consequences of this on dendritic cell function in relation to human cancer. This review also aims to foster a better understanding of the host mediated immunological mechanisms which may be potentially manipulated in cancer patients undergoing oral chemotherapy.


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Inhibitors of Cyclin Dependent Kinases: Useful Target for Cancer Treatment
P. Sapra Sharma, R. Sharma and R. Tyagi

Cancer drug discovery is one of the most rapidly changing areas of pharmaceutical research. 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 Cyclin Dependent Kinases (CDKs) is one of the mechanisms underlying the physiological hyper-proliferation. CDKs are serine/threonine protein kinases, which play an important role in cell-cycle regulation. Their sequential activation ensures, the correct timing and ordering of events required for cell cycle progression. Therefore, inhibition of CDKs, through the insertion of small molecules into its ATP binding pocket has emerged as a potential therapy method for cancers. 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.


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Small Molecule Tyrosine Kinase Inhibitors: Potential Rol in Pediatric Malignant Solid Tumors
Jochen Rössler, Birgit Geoerger, Melissa Taylor and Gilles Vassal

Tyrosine kinase receptors are expressed on the surface of tumor and/or endothelial cells and represent attractive targets for new anti-cancer treatment strategies. The so-called “small molecule” tyrosine kinase inhibitors have been designed to interact with the intracellular ATP binding site of these receptors, subsequently causing arrest of tumor cell proliferation, as well as induction of apoptosis and tumor migration. Furthermore, these molecules can impact on tumor angiogenesis. Tyrosine kinase inhibitors have been evaluated in several clinical trials for various adult malignant tumor entities and are currently being studied in pediatric solid malignancies. In this review, we will address the data available supporting the potential use of tyrosine kinase inhibitors in solid malignancies of childhood.