Current Cancer Drug Targets - Volume 4, Issue 3, 2004

The serine / threonine kinase Akt functions intracellularly as a cardinal nodal point for a constellation of converging upstream signaling pathways, which involve stimulation of receptor tyrosine kinases such as IGF-1R, HER2 / Neu, VEGF-R, PDGF-R), and an assembly of membrane-localized complexes of receptor-PI-3K and activation of Akt through the second messenger PIP3. The integration of these intracellular signals at the level of Akt and its kinase activity, regulates the phosphorylation of its several downstream effectors, such as NF-κB, mTOR, Forkhead, Bad, GSK-3 and MDM-2. These phosphorylation events in turn mediate the effects of Akt on cell growth, proliferation, protection from pro-apoptotic stimuli, and stimulation of neoangiogenesis. Because Akt and its upstream regulators are deregulated in a wide range of solid tumors and hematologic malignancies, and in view of the aforementioned biologic sequelae of this pathway, the Akt pathway is considered a key determinant of biologic aggressiveness of these tumors, and a major potential target for novel anti-cancer therapies. This review focuses on ongoing translational efforts to therapeutically target Akt and its biologic sequelae, either at the level of Akt itself or at the levels of its upstream regulators and downstream effectors. Because Akt is also important for proliferative and anti-apoptotic signaling pathways critical for normal cells, particular emphasis is placed on the fine-tuning the targeting of individual components of this pathway to maximize the therapeutic index of anti-cancer strategies based on the PI-3K / Akt pathway.

The cytochrome P450s are an essential group of enzymes involved in metabolism of drugs, foreign chemicals, arachidonic acid, cholesterol, steroids and other important lipids. The cytochrome P450 enzyme system is responsible for much of the phase I metabolism of chemotherapeutic agents. At the simplest level the detoxification properties of the cytochrome P450s are used to help clear a cytotoxic before it results in serious irreversible toxicity to the patient while at other levels the cytochrome P450s are involved to varying extents in drug bioactivation. This metabolism primarily occurs in organs and tissues of the body known to express cytochrome P450 ubiquitously (i.e. liver and gastrointestinal tract), but there is also evidence to suggest that it occurs within the tumor microenvironment due to localized, tumor specific expression of certain P450 isoforms. Several of today's currently prescribed cytotoxics (e.g. cyclophosphamide and tamoxifen) undergo systematic bioactivation by cytochrome P450, which often results in toxicity to the patient. The realization that many tumors have differential cytochrome P450 expression when compared to the corresponding normal tissue has allowed the rational design of the next generation of cytotoxic around cytochrome P450 enzymology. Several new agents now entering clinical trials (e.g. Phortress and AQ4N) are specifically designed to exploit tumor cytochrome P450, resulting in local bioactivation of the cytotoxic at the tumor site. Specific activation of pro-drugs by isoforms whose expression or particular catalytic activity is limited to cancer cells offers the possibility of truly targeted chemotherapy with minimized systemic toxicity.

Leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme with the activities of epoxide hydrolase and aminopeptidase. As an epoxide hydrolase, LTA4H catalyzes the hydrolysis of the epoxide LTA4 to the diol, leukotriene B4 (LTB4), which mainly functions as a chemoattractant and an activator of inflammatory cells. As an aminopeptidase, LTA4H may process peptides related to inflammation and host defense. In a chronic inflammation-associated animal model of esophageal adenocarcinoma, we have shown that LTA4H was overexpressed in tumor as compared to normal tissues. Bestatin, an LTA4H inhibitor, suppresses tumorigenesis in this animal model. Since LTA4H has long been regarded as an anti-inflammatory target, we propose LTA4H as a target for prevention and therapy of cancers, especially those associated with chronic inflammation. Here we review the gene structure, expression, regulation and functions of LTA4H, as well as its involvement in carcinogenesis. We believe LTA4H / LTB4 may play an important role in chronic inflammation associated carcinogenesis by at least two mechanisms: a) the inflammation-augmenting effect on inflammatory cells through positive feedback mediated by its receptors and downstream signaling molecules; and b) the autocrine growth-stimulatory effect of LTB4 produced by epithelial cells, and the paracrine growthstimulatory effect of LTB4 produced by inflammatory cells, on precancerous and cancer cells. Based on our present knowledge, inhibitors of LTA4H or antagonists of LTB4 receptors may be used alone or in combination with other agents (e.g., cyclooxygenase 2 inhibitors) in cancer prevention and treatment trials to test their effectiveness.

We review the therapeutic and preventive applications of a retinoid analog (vitamin A and its derivatives) for human cancers. Chemoprevention of cancer is an intervention in the carcinogenic process by chemical agents that block or reverse the malignant transformation of cells. Retinoids are prime candidates for cancer chemoprevention since cancer is characterized by abnormal growth with a lack of differentiation, which could be modified by retinoids. Retinoids exert their biological functions through nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR). A number of experimental and clinical studies have been performed in the past two decades with retinoids showing that they inhibit or reverse the carcinogenic process in some organs, including hematological malignancy as well as premalignant and malignant lesions in the oral cavity, head and neck, breast, skin and liver. We particularly focus upon the therapeutic application of alltrans RA (atRA) to acute promyelocytic leukemia (APL) and on the preventive approach to hepatocellular carcinoma (HCC) by a synthetic retinoid analog, acyclic retinoid. In both malignancies, malfunction of retinoid nuclear receptors is closely related to their carcinogenic process. In APL, a chromosomal translocation produces a chimeric protein between RARα and a protein called promyelocyte leukemia protein (PML). PMLRARα works as a dominant negative receptor in the leukemic cells, interfering with the normal function of RARα and / or PML, which in turn results in the arrest of cell maturation at the stage of promyelocytes. Oral administration of atRA induces differentiation of promyelocytic leukemic cells to mature neutrophils, and leads to a high rates (over 90%) of complete remission. AtRA therapy has become standard in the treatment of APL. In the case of HCC, post-translational modification of RXR by phosphorylation impairs its function, which leads to uncontrolled cell growth. Acyclic retinoid suppresses the phosphorylation of RXR?, restores its function in the presence of its endogenous ligand, 9-cis RA, and thereby induces apoptosis of the cancer cells. Acyclic retinoid given orally successfully suppresses the development of second primary tumors in cirrhotic patients who undergo curative removal of preceding HCC. Eradication of (pre)malignant clones ('clonal deletion') from the liver is suggested as a mechanism of the chemopreventive effect. Further development of more effective retinoids as well as their use in combination with other classes of anticancer agents including immunopreventive drugs like interferons may provide strategies for cancer prevention.

Protein synthesis plays an important role in the regulation of cell proliferation. While the role of cap-dependent translation in cell transformation has been studied extensively another translation initiation mechanism, internal initiation of cellular mRNAs, emerged recently and is relatively unappreciated and poorly understood. Internal initiation is mediated by IRES elements that are found in the 5' untranslated region (5' UTR) of mRNA. Curiously, several oncogenes, growth factors and proteins involved in the regulation of programmed cell death contain IRES elements in their 5' UTRs. Internal initiation escapes many control mechanisms that regulate cap-dependent translation. In this review I will discuss the data supporting the hypothesis that selective translation of these factors may contribute to the survival of cancer cells under stressful situations, such as lack of nutrients, hypoxia, or therapy-induced DNA damage and contributes to the development and progression of cancer and to the establishment of cancer cells that are resistant to conventional therapies.