Current Cancer Drug Targets, Volume 4, No. 3, 2004
Contents
The Akt Pathway: Molecular Targets for Anti-Cancer
Drug Development Pp.235-256
The Role of Cytochrome P450 in Cytotoxic
Bioactivation: Future Therapeutic Directions Pp.257-265
P.H.
Rooney, C. Telfer, M.C.E. McFadyen, W.T. Melvin and G.I. Murray
Leukotriene A4 Hydrolase as a Target for
Cancer Prevention and Therapy Pp.267-283
X.
Chen, S. Wang, N. Wu and C.S. Yang
Retinoids in Cancer Chemoprevention Pp.285-298
Masataka
Okuno, Soichi Kojima, Rie Matsushima-Nishiwaki, Hisashi Tsurumi, Yasutoshi
Muto, Scott L. Friedman and Hisataka Moriwaki
Targeting Translation for Treatment of Cancer
- A Novel Role for IRES? Pp.299-311
Martin
Holcik
Abstracts
[Back to top] The Akt
Pathway: Molecular Targets for Anti-Cancer Drug Development
Constantine S. Mitsiades, Nicholas Mitsiades and Michael Koutsilieris
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-kB, 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 neo-angiogenesis. 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.
[Back to top] The Role of Cytochrome P450 in Cytotoxic
Bioactivation: Future Therapeutic Directions
P.H.
Rooney, C. Telfer, M.C.E. McFadyen, W.T. Melvin and G.I. Murray
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.
[Back to top] Leukotriene A4
Hydrolase as a Target for Cancer Prevention and Therapy
X.
Chen, S. Wang, N. Wu and C.S. Yang
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.
[Back to top] Retinoids in Cancer Chemoprevention
Masataka
Okuno, Soichi Kojima, Rie Matsushima-Nishiwaki, Hisashi Tsurumi, Yasutoshi
Muto, Scott L. Friedman and Hisataka Moriwaki
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 RXRα, 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.
[Back to top] Targeting Translation for Treatment of Cancer
- A Novel Role for IRES?
Martin
Holcik
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.