Contents
Novel Approaches for Targeted Cancer Therapy Pp.313-326
Veronique
Guillemard and H. Uri Saragovi
Signaling Pathways Responsible for Cancer
Cell Invasion as Targets for Cancer Therapy Pp.327-336
Daniel
Sliva
Functional Antagonism between NF-κB and
Nuclear Receptors: Implications in Carcinogenesis and Strategies for Optimal
Cancer Chemopreventive Interventions Pp.337-344
V.B.
Andela
Microfilament Actin Remodeling as a Potential
Target for Cancer Drug Development Pp.345-354
JianYu
Rao and Ning Li
Vitamin E Analogues: A New Class of Inducers
of Apoptosis with Selective Anti-Cancer Effects Pp.355-372
Jiri Neuzil, Marco Tomasetti, Albert S. Mellick, Renata Alleva, Brian A. Salvatore, Marc Birringer and Marc W. Fariss
Potent Chemopreventive Agents Against
Pancreatic Cancer Pp.373-384
Akiyoshi Nishikawa, Fumio Furukawa, In-Seon Lee, Takuji Tanaka and Masao Hirose
[Back to top] Novel
Approaches for Targeted Cancer Therapy
Veronique Guillemard and H. Uri Saragovi
The clinical use
of chemotherapeutic agents against malignant tumors is successful in many cases
but suffers from major drawbacks. One drawback is lack of selectivity, which
leads to severe side effects and limited efficacy; and another is the
emergence/selection of drug-resistance. To limit non-specific toxicity and to
improve the efficiency of cancer therapy, “tumor markers”, which are proteins
generally overexpressed on the surface of tumor cells, can be selectively
targeted. Growth factor receptors are one of the most extensively studied tumor
markers. The implication of growth factor receptors in the pathogenesis and
evolution of cancer has clearly been established and therefore, provides a
rationale for therapeutic intervention. The targeting of cytotoxic substances
to tumor markers with “magic bullets” is an old idea that raised high
expectations but also disappointment. Over the past decade, newly gained
understanding of mechanisms for targeted therapy have brought new hopes.
Pharmacological agents that selectively target and block the action of growth
factors and their receptors have been attempted, such as monoclonal antibodies
(mAbs) (whole molecule or fragments), bispecific antibodies, mAbs conjugated to
drugs, toxins or radioisotopes, small peptidic and peptidomimetic molecules in
free form or conjugated to drugs, anti-sense oligonucleotides, immunoliposomes-encapsulated
drugs, and small molecule inhibitors. This review will focus on current
developments of selective targeting and bypassing drug resistance in the
management of growth factor receptor-overexpressing tumors.
[Back to top] Signaling Pathways Responsible for Cancer
Cell Invasion as Targets for Cancer Therapy
Daniel
Sliva
Migration of
cancer cells is one of the key factors responsible for cancer metastasis. The
elucidation of mechanisms responsible for the highly invasive potential of
cancer cells can help to identify specific targets for the treatment of cancer
patients. Highly invasive cancers are usually characterized by aberrant
activity of specific intra- or extracellular molecules such as protein kinases,
phosphatases, transcriptional factors, proteolytic enzymes, and others. Protein
kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) are responsible for the
constitutive activity of transcriptional factors NF-κB and AP-1 in some of
the highly invasive cancers. Furthermore, NF-κB and AP-1 control the
expression of urokinase-type plasminogen activator (uPA) and its receptor
(uPAR), and expression of both uPA and uPAR correlates with invasive cancer
cell phenotype and poor prognosis. The inhibition of PKC and PI3K signaling
(through NF-κB and AP-1) suppressed the secretion of uPA, resulting in the
inhibition of motility of highly invasive breast cancer cells. Therefore,
inhibition of specific target molecules in common signaling pathway(s)
responsible for metastatic spread can have potential clinical relevance. This
review will summarize different approaches to targeting distinct signaling
molecules involved in cancer invasion and metastasis.
[Back to top] Functional Antagonism between NF-κB and
Nuclear Receptors: Implications in Carcinogenesis and Strategies for Optimal
Cancer Chemopreventive Interventions
V.B.
Andela
Hyper-activation
of nuclear factor kappa B (NF-κB) is germane to carcinogenesis by its fundamental
implication in cellular de-differentiation and proliferation, the subversion of
apoptosis, the promotion of neo-angiogenesis, invasive growth and metastases.
Conversely, the expression of multiple nuclear receptors (NRs), arbiters of
cellular differentiation, decreases with progressive carcinogenesis. This
review is a conceptual discussion of evidence to support NF-κB as the
nexus between carcinogenesis and decreased NR expression. Furthermore, it
synthesizes the thesis and antithesis of NR function in carcinogenesis and
expounds on the functional antagonism between NRs and NF-κB as a basis for
the chemopreventive activity of NR ligands. Finally, strategies for optimal
chemopreventive interventions with NR ligands are discussed.
[Back to top]
Microfilament Actin Remodeling as a Potential Target for
Cancer Drug Development
JianYu
Rao and Ning Li
Actin was first
identified in non-muscle cells only about three decades ago, and at about the
same time, it was found that actin filaments were disrupted in the malignant
transformed cells. The actin network is a rather complex, yet important
structural and functional system of all eukaryotic cells. Actin filaments
provide the basic infrastructure for maintaining cell morphology and functions
such as adhesion, motility, exocytosis, endocytosis, and cell division. Growing
evidence from this laboratory and others shows that alterations of actin
polymerization, or actin remodeling, plays a pivotal role in regulating the
morphologic and phenotypic events of a malignant cell. Actin remodeling is the
result of activation of oncogenic actin signaling pathways (e.g., Ras and Src),
or inactivation of several important actin-binding proteins that have tumor
suppressor functions (e.g., gelsolin). Distinctive protein expression patterns
of some of these genes in cancer and progressive carcinogenic processes have
been observed. It has become evident that actin dynamics are regulated by a
complex interplay of the small GTPase proteins of Ras superfamily Rac, Rho, and
Cdc42, and efforts to develop specific inhibitors for these small G proteins as
anticancer drug are underway. In this review we will discuss how actin
remodeling is altered in the malignant transformation process, the functional
significance of actin alteration in association with malignant phenotypes, and
the approaches of targeting actin remodeling for chemopreventive and
chemotherapeutic drug development. Approaches including using nature products
directly modulating actin polymerization, using inhibitors of actin pathway
small G proteins, and using gene-augmentation for actin binding proteins will
be discussed. In addition, the concept of using F/G-actin ratio as a surrogate
marker for actin-pathway based therapy will also be introduced.
[Back to top] Vitamin E Analogues: A New Class of Inducers
of Apoptosis with Selective Anti-Cancer Effects
Jiri
Neuzil, Marco Tomasetti, Albert S. Mellick, Renata Alleva, Brian A. Salvatore, Marc
Birringer and Marc W. Fariss
In spite of
unrelenting effort, the net incidence of neoplastic diseases appears not to
have been curbed. While some types of cancer have been suppressed
significantly, others are either stagnating or on the increase. Therefore, the
need for a cure is imperative, in particularly a drug or combination of drugs
that would be selective for malignant cells, i.e. with as low secondary
toxicity as possible. Recent data strongly suggest that analogues of vitamin E,
epitomised by the most studied a-tocopheryl
succinate (a-TOS), may meet the need for the coveted
drugs with a selective anti-neoplastic effect. The reasons for this optimism
are reviewed in this article.
[Back to top] Potent Chemopreventive Agents Against
Pancreatic Cancer
Akiyoshi
Nishikawa, Fumio Furukawa, In-Seon Lee, Takuji Tanaka and Masao Hirose
Development of pancreatic cancers is
clinically so silent in general that at the time of diagnosis, the vast
majority of cases are incurable with a very poor prognosis. Therefore,
effective preventive approaches against this aggressive disease are urgently
required. Experimentally, carcinogenesis process is assumed to consist of at
least two stages named initiation and promotion. Using a two-stage model of
hamster pancreatic carcinogenesis, we have reported stage-specific inhibitory
effects by a number of potent cancer chemopreventive agents. Among them,
phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables,
remarkably blocked the initiation phase of pancreatic as well as lung
carcinogenesis in hamsters initiated with N-nitrosobis(2-oxopropyl)amine
(BOP). However, PEITC failed to affect both pancreatic and lung carcinogenesis
when given during the post-initiation (promotion) phase of carcinogenesis. In
contrast, our recent study clearly demonstrated that a cyclooxygenase (COX)-2
inhibitor substantially protects against BOP-induced pancreatic tumors in
hamsters in line with decrease in cell proliferative activity of pancreatic
ducts when given in the post-initiation phase. Interestingly, trypsin
inhibitors inhibited both initiation and post-initiation phases of BOP-induced
pancreatic carcinogenesis although they are known to induce hyperplastic acinar
lesions in the rat pancreas. Taken together with these data, our review is
aimed at looking over mechanistic insights into potent chemopreventive agents
against pancreatic cancer.