Contents
The MYC Oncogene as a Cancer Drug Target Pp.163-175
Heiko
Hermeking
Gab1, SHP-2 and Other Novel Regulators of
Ras: Targets for Anticancer Drug Discovery? Pp.177-192
Armelle
Yart , Patrick Mayeux and Patrick
Raynal
Taxanes: Microtubule and Centrosome Targets,
and Cell Cycle Dependent Mechanisms of Action Pp.193-203
M.
Abal , J. M. Andreu and
Tumor Angiogenesis: A Potential Target In
Cancer Control by Phytochemicals Pp.205-217
Rana
P. Singh and Rajesh Agarwal
Short-Chain Fatty Acid Inhibitors of Histone
Deacetylases: Promising Anticancer Therapeutics? Pp.219-236
James S. Chen , Douglas V. Faller , and Remco A. Spanjaard
[Back to top] The
MYC Oncogene as a Cancer Drug Target
Heiko Hermeking
The universal
deregulation of c-myc gene expression in tumor cells suggests that this oncogene
represents an attractive target for cancer therapeutic purposes. The same
applies to the N-myc gene, which has a more restricted tissue specificity.
Translocation (e.g., c-myc in Burkitt’s lymphoma), or amplification (e.g.,
N-myc in neuroblastoma) of myc genes has been causally linked to tumor
formation. Furthermore, the c-myc promoter integrates diverse mitogenic
signalling cascades, which are constitutively activated in tumor cells, and
translates them into expression of the c- MYC transcription factor, which
promotes cell proliferation by regulating the expression of numerous target
genes. Recent experimental data suggest, that even a brief inhibition of c-myc
expression may be sufficient to permanently stop tumor growth and induce
regression of tumors. Attempts to identify specific inhibitors of c-MYC/MAX
dimerization have yielded promising results. In addition, downstreamtarget
genes of c-MYC represent attractive targets for tumor therapy. Tumor cells
expressing c-MYC at elevated levels are sensitized to treatment with
DNA-damaging drugs. In mice and presumably also in human patients, the
successful treatment of c-myc-induced tumors with conventional chemotherapy
depends on the presence of functional p53. Therefore, restoration of this
pathway, which is commonly lost in cancer cells, may enhance therapy of
c-myc-induced tumors. These and other recent developments, which address the
use of myc genes as therapeutic targets for cancer treatment, are discussed in
this review.
[Back to top] Gab1, SHP-2 and Other Novel Regulators of
Ras: Targets for Anticancer Drug Discovery?
Armelle
Yart , Patrick Mayeux and Patrick
Raynal
Ras proteins
function as molecular switches that cycle between an inactive GDP-bound state,
and an active GTP-bound form that triggers different signaling pathways.
Because Ras can integrate both proliferative and anti-apoptotic stimuli,
GTP-locked Ras mutants play a critical role in the development of human tumors.
Moreover, wild-type Ras relays the transforming potential of a number of
molecules involved in tumor development, including protein tyrosine kinases.
Consequently, the molecular intermediates that control Ras activation are
potential targets of anti-tumoral pharmacology. Besides the canonical
Shc/Grb2/Sos module classically involved in Ras activation, novel effectors
have recently been shown to participate in this pathway, including the
multivalent Grb2-associated docking protein Gab1, the protein tyrosine
phosphatase SHP-2, and the phosphoinositide 3-kinase. Recent genetic advances
have shown that these proteins are critically involved in cell proliferation
and survival, further suggesting that they could be interesting targets for
selective tumor therapy. Here we review recent progress in our understanding of
the role of Gab1 and its partners in Ras activation, and other
survival/proliferation pathways. Implications for the pharmacological
manipulation of this pathway in the treatment of cancer will also be discussed.
[Back to top] Taxanes: Microtubule and Centrosome Targets,
and Cell Cycle Dependent Mechanisms of Action
Microtubules are
highly dynamic cellular polymers made of αβ-tubulin and associated
proteins. They play a key role during mitosis, participating in the exact
organization and function of the spindle, and are critical for assuring the
integrity of the segregated DNA. Therefore, they represent one of the more
effective targets in current cancer therapy.
Paclitaxel
(Taxol®) is the prototype of the taxane family of antitumor drugs, and it was
the first natural product shown to stabilize microtubules. This unique
mechanism of action is in contrast to other microtubule poisons, such as Vinca
alkaloids, colchicine, and cryptophycines, which inhibit tubulin
polymerization. Taxanes block cell cycle progression through centrosomal
impairment, induction of abnormal spindles and suppression of spindle
microtubule dynamics. Triggering of apoptosis by aberrant mitosis or by
subsequent multinucleated G1-like state related to mitotic slippage, depends on
cell type and drug schedule.
The development of
fluorescent derivatives of paclitaxel led us to locate spindle pole
microtubules and centrosomes as main sub-cellular targets of cytotoxic taxoids
in living cells. In this review we discuss these findings in the context of a
cell cycle-dependent response to taxanes, based on the cellular targets, and
the status of the implicated cell cycle checkpoints. We also review those
events that can influence this response, like the different signal transduction
pathways activated/inactivated in relation to Bcl-2 phosphorylation and
induction of apoptosis, and the controversial role of the p53 status on cell
sensitivity to paclitaxel. Finally, cell cycle-dependent resistance, an
emerging concept in combination sequential chemotherapy, is discussed on the
basis of the cell cycle-dependent mechanisms of action of taxanes.
[Back to top] Tumor Angiogenesis: A Potential Target In Cancer
Control by Phytochemicals
Rana P. Singh and
Rajesh Agarwal
It is now well
established that angiogenesis is an obligatory event for the growth and
progression of solid tumors beyond the size limit (~2 mm diameter) imposed by
simple diffusion for the nutrient supply. Human tumors can remain dormant for
years owing to a balance between cell proliferation and apoptosis. Several
hypotheses have been articulated regarding the critical importance of tumor
angiogenesis in the development and metastatic spread of tumors, and how
preventive/therapeutic inhibition of angiogenesis might be exploited as a novel
means of controlling cancer growth. Anti-angiogenic therapy is suggested as one
of the most promising approaches to control cancer, as endothelial cells are
generally non-transformed cells and are less prone to acquire drug resistance.
Tumor vasculature could be an important prognostic marker, and an independent
predictor of pathologic stages and malignant potential of cancer. This review
is focused on recent developments and comprehensive mechanistic aspects of
phytochemicals related to an interplay of angiogenic promoters and inhibitors,
and associated signaling in both tumor as well as endothelial cells. Since,
vascular endothelial cells constitute the first line exposure to the
blood-borne agents, it is plausible that anti-angiogenic activity of
phytochemicals could be associated with lowering the risk of cancer by
preventing the growth and metastasis of tumor.
[Back to top] Short-Chain Fatty Acid Inhibitors of Histone
Deacetylases: Promising Anticancer Therapeutics?
James
S. Chen , Douglas V. Faller , and Remco A. Spanjaard
Cancer is a
disease in which cellular growth regulatory networks are disrupted. Lesions in
wellcharacterized oncogenes and tumor suppressors often contribute to the
dysregulation, but recent work has also uncovered the fundamental importance of
enzymes that modulate the acetylation status of chromatin to the initiation or
progression of cancer. Histone acetyltransferases (HATs) and histone
deacetylases (HDACs) are known to be involved in physiological cellular
processes, such as transcription, cell cycle progression, gene silencing,
differentiation, DNA replication, and genotoxic responses, but they are also
increasingly being implicated in tumorigenesis. Butyrate is a short-chain fatty
acid (SCFA) that acts as a HDAC inhibitor and is being clinically evaluated as
an anti-neoplastic therapeutic, primarily because of its ability to impose cell
cycle arrest, differentiation, and/or apoptosis in many tumor cell types, and
its favorable safety profile in humans. Additionally, HDAC inhibitors could be
used in combination with certain established antitumor therapeutics, such as
those that target transcription, to augment clinical efficacy, and/or reduce
toxicity. The molecular pathways of butyrate and related next-generation
synthetic SCFAs in mediating these effects have not been fully elucidated, but
HDAC inhibition is associated with regulation of critical cell cycle
regulators, such as cyclin D, p21CIP1/WAF1, and p27KIP1.
It is anticipated that a better understanding of this critical intersection
between SCFAs, HDACs, and cell cycle control will lead to the design of novel
treatment strategies for neoplasias. This review will summarize some of the
recent research in these arenas of HDAC-directed cancer therapy and discuss the
potential application of these agents in synergy with current
chemotherapeutics.