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Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 10, Number 2, February 2010
Contents
Recent Concepts on Cancer- and Metastasis-Initiating
Cells and Their Therapeutic Implications in the Development
of Novel Effective Cancer Therapies
Guest Editors: M. Mimeault and S.K. Batra
Editorial Pp.
103
Targeting the Acute Myeloid Leukemia Stem Cells Pp.
104-110
A. Krause, L.M.F. Krause and E.M. Rego
[Abstract] [Purchase
Article]
Novel Therapeutic Agents Against Cancer Stem Cells
of Chronic Myeloid Leukemia Pp. 111-115
Y. Chen, C. Peng, C. Sullivan, D. Li and
S. Li
[Abstract] [Purchase
Article]
Multiple Myeloma: A Paradigm for Translation of the Cancer
Stem Cell Hypothesis Pp. 116-120
J.R. Agarwal and W. Matsui
[Abstract] [Purchase
Article]
Gliomagenesis and the Use of Neural Stem Cells in
Brain Tumor Treatment Pp. 121-130
P. Achanta, N.I.S. Roman and A. Quiñones-Hinojosa
[Abstract] [Purchase
Article]
Tumor Initiation in Human Malignant Melanoma and Potential
Cancer Therapies Pp. 131-136
J. Ma and M.H. Frank
[Abstract] [Purchase
Article]
Novel Therapies Against Aggressive and Recurrent Epithelial
Cancers by Molecular Targeting Tumor- and Metastasis-Initiating
Cells and Their Progenies Pp. 137-151
M. Mimeault and S.K. Batra
[Abstract] [Purchase
Article]
Potential Targets for Improving Radiosensitivity of
Breast Tumor-Initiating Cells Pp. 152-156
W. Xu, B.G. Debeb, L. Lacerda and W.A. Woodward
[Abstract] [Purchase
Article]
Targeting Ovarian Cancer-Initiating Cells
Pp. 157-163
S.K. Murphy
[Abstract] [Purchase
Article]
Lung Cancer Stem Cells as a Target for Therapy
Pp. 164-171
E. Gorelik, A. Lokshin and V. Levina
[Abstract] [Purchase
Article]
Liver Cancer Stem Cells as an Important Target in
Liver Cancer Therapies Pp. 172-175
G.-M. Zou
[Abstract] [Purchase
Article]
General Articles
Gestational Trophoblastic Neoplasia, an Ancient Disease:
New Light and Potential Therapeutic Targets Pp.
176-185
M. Alazzam, J. Tidy, B.W. Hancock and H.J. Powers
[Abstract] [Purchase
Article]
Abstracts
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Editorial:
New concepts on carcinogenesis process suggest that
the malignant transformation of adult stem/progenitor cells
and/or their progenies endowed with stem cell-like properties
into highly leukemic or tumorigenic cancer stem/progenitor
cells may provide critical functions in cancer initiation
and progression to locally invasive and metastatic cancers,
treatment resistance and disease relapse [1, 2]. In support
with this hypothesis, the cancer stem/progenitor cells, also
designated as cancer-, leukemia-, tumor- or metastasis-initiating
cells endowed with stem cell-like properties have been identified
and isolated from a variety of human primary and metastatic
cancers and established cancer cell lines [1, 2]. It has been
shown that these immature cancer cells with high self-renewal
potential and aberrant differentiation ability were able to
giving rise to the total cancer cell mass that recapitalized
the histological and cytological architecture of original
patient’s leukemias or tumors [1, 2].
In addition, numerous accumulating lines of experimental evidence
have also revealed that the resistance of cancer stem/progenitor
cells to current anti-hormonal, radiation and chemotherapeutic
treatments may lead to their persistence at the primary cancers
and metastatic sites after therapy initiation and disease
recurrence [1, 2]. Therefore, the development of novel targeted
approaches to eradicating the total cancer cell mass, including
highly leukemic or tumorigenic cancer stem/progenitor cells
and their progenies, is of immense clinical interest for improving
current cancer treatments. These novel combination therapies
should be effective to treat the patients diagnosed with advanced
cancers, and thereby prevent disease relapse and the death
of cancer patients [2].
In this special issue, the experimented researchers specialized
on different aspects related to carcinogenesis process and
drug development research will review for us the most recent
advancements on the identification of immature cancer cells
with the stem cell-like properties in different aggressive
and recurrent cancer types. The therapeutic implications of
these recent progresses for the development of novel effective
cancer therapies will also be discussed. More specifically,
novel potential therapeutic drug targets in cancer- and metastasis-initiating
cells and their progenies and important foundings in the development
of novel pharmacological agents for eradicating the cancer
stem/progenitor cells and improving the current clinical cancer
treatments will be reviewed.
The subtopics covering in this special issue include leukemia-initiating
cells (acute myeloid leukemia “AML” and chronic
myeloid leukemia “CML”) as well as diverse tumor-
and metastasis-initiating cells involved in multiple myeloma,
brain and melanoma and diverse epithelial tumors such as prostate,
pancreas, breast, ovarian, lung and liver cancers. Especially,
the emphasis is on the critical functions of these immature
cells in cancer initiation and progression, metastases at
distant tissues, treatment resistance and disease relapse.
Of therapeutic interest, potential therapeutic drug targets
in cancer-initiating cells and novel targeted therapies and
combination cancer therapies will be reviewed. Moreover, the
importance to also consider the molecular targeting of host
tumor microenvironment of cancer stem/progenitor cells is
also discussed. Other promising therapeutic approaches to
treat cancer patients discussed in this special issue also
include novel stem cell-based cancer therapies, selective
delivery strategies of anti-cancer drugs (nanoparticule- and
liposome-based systems), anti-angiogenic treatments and immunotherapies.
Taken together, information provided in this special issue
should help researchers to develop novel combination therapies
by molecular targeting of both highly tumorigenic cancer stem/progenitor
cells and their progenies for a most effective treatment of
cancer patients diagnosed at early and late stages with aggressive,
metastatic and lethal cancers.
REFERENCES
[1] Mimeault, M.; Batra, S.K. New advances on critical implications
of tumor- and metastasis-initiating cells in cancer progression,
treatment resistance and disease recurrence. Histol. Histopathol.,
2010, (in press).
[2] Mimeault, M.; Batra, S.K., New promising drug targets
in cancer- and metastasis-initiating cells. Drug Discov.
Today, 2010, (in press).
M. Mimeault and S.K. Batra
Guest Editors
Anti-Cancer Agents in Medicinal Chemistry
Department of Biochemistry and Molecular Biology and
Eppley Institute for Research in Cancer and Allied Diseases
University of Nebraska Medical Center,
Omaha, NE 68198-5870
USA
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Article]
Targeting the Acute Myeloid Leukemia Stem Cells
A. Krause, L.M.F. Krause and
E.M. Rego
The idea that within the bulk of leukemic cells there are
immature progenitors which are intrinsically resistant to
chemotherapy and able to repopulate the tumor after treatment
is not recent. Nevertheless, the term leukemia stem cells
(LSCs) has been adopted recently to describe these immature
progenitors based on the fact that they share the most relevant
features of the normal hematopoetic stem cells (HSCs), i.e.
the self-renewal potential and quiescent status. LSCs differ
from their normal counterparts and from the more differentiated
leukemic cells regarding the default status of pathways regulating
apoptosis, cell cycle, telomere maintenance and transport
pumps activity. In addition, unique features regarding the
interaction of these cells with the microenvironment have
been characterized. Therapeutic strategies targeting these
unique features are at different stages of development but
the reported results are promising. The aim of this review
is, by taking acute myeloid leukemia (AML) as a bona fide
example, to discuss some of the mechanisms used by the LSCs
to survive and the strategies which could be used to eradicate
these cells.
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Article]
Novel Therapeutic Agents Against Cancer Stem Cells of Chronic
Myeloid Leukemia
Y. Chen, C. Peng, C. Sullivan, D. Li and
S. Li
TChronic myeloid leukemia (CML) is induced by the BCR-ABL
oncogene, a product of Philadelphia (Ph) chromosome. The BCR-ABL
kinase inhibitor imatinib is a standard treatment for Ph+
leukemia, and has been shown to induce a complete hematologic
and cytogenetic response in most chronic phrase CML patients.
However, imatinib does not cure CML, and one of the reasons
is that imatinib does not kill leukemia stem cells (LSCs)
in CML both in vitro and in vivo. Recently,
several new targets or drugs have been reported to inhibit
LSCs in cultured human CD34+
CML cells or in mouse model of BCR-ABL induced CML, including
an Alox5 pathway inhibitor, Hsp90 inhibitors, omacetaxine,
hedgehog inhibitor and BMS-214662. Specific targeting of LSCs
but not normal stem cell is a correct strategy for developing
new anti-cancer therapies in the future.
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Article]
Multiple Myeloma: A Paradigm for Translation of the
Cancer Stem Cell Hypothesis
J.R. Agarwal and W. Matsui
Despite recent advances in drug development, multiple myeloma
(MM) remains incurable for the majority of patients due to
relapse and disease progression. The cancer stem cell (CSC)
hypothesis may provide an explanation for these clinical findings.
It suggests that the long-term proliferative potential responsible
for disease initiation, maintenance, and relapse is contained
within specific subpopulations of biologically distinct tumor
cells. Data in MM suggest that CSCs represent a rare cell
population phenotypically resembling normal memory B cells.
Compared to MM plasma cells, MM CSCs also appear to be relatively
resistant to a wide variety of standard anti-cancer agents
suggesting they may persist following treatment and mediate
tumor re-growth and relapse. A unique property CSCs share
with their normal counterparts is the potential for self-renewal
that likely maintains the malignant clone over time. The development
of therapeutic strategies targeting the signaling elements
contributing to cancer cell self-renewal has been limited
primarily because the cellular processes involved are poorly
understood. However, it is common that the signaling pathway
components regulating normal stem cell self-renewal are aberrantly
activated in human cancers and may serve as potential therapeutic
targets. One class of shared regulatory pathways are those
active during normal embryonic patterning and organ formation
such as Hedgehog (Hh), Notch and Wingless (Wnt), and emerging
data suggest that these may play a role in CSCs. Here we review
the identification and characterization of MM CSCs, the role
of Hh in MM, and issues to be considered during the early
clinical testing of CSC targeting agents.
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Article]
Gliomagenesis and the Use of Neural Stem Cells in
Brain Tumor Treatment
P. Achanta, N.I.S. Roman and A. Quiñones-Hinojosa
The role of neural stem cells (NSCs) in both the physiological
and pathological processes in the brain has been refined through
recent studies within the neuro-oncological field. Alterations
in NSC regulatory mechanisms may be fundamental for the development
and progression of malignant gliomas. A subpopulation of cells
within the tumor known as brain tumor stem cells (BTSCs) have
been shown to share key properties with NSCs. The BTSC hypothesis
has significantly contributed to a potential understanding
as to why brain tumors hold such dismal prognosis. On the
other hand, the normal NSCs possess the capacity to migrate
extensively towards the tumor bulk as well as to lingering
neoplastic regions of the brain. The tropism of NSCs towards
brain tumors may provide an additional tool for the treatment
of brain cancer. The creation of potential therapies through
the use of NSCs has been studied and includes the delivery
of gene products to specific locations of the central nervous
system selectively targeting malignant brain tumor cells and
maximizing the efficiency of their delivery. Here, the proposed
mechanisms of how brain tumors emerge, the molecular pathways
interrupted in NSC pathogenesis and the most recent preclinical
results in the use of NSCs for glioma treatment are reviewed.
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Article]
Tumor Initiation in Human Malignant Melanoma and Potential
Cancer Therapies
J. Ma and M.H. Frank
Cancer stem cells (CSCs), also known as tumor-initiating cells,
have been identified in several human malignancies, including
human malignant melanoma. The frequency of malignant melanoma-initiating
cells (MMICs), which are identified by their expression of
ATP-binding cassette (ABC) family member ABCB5, correlates
with disease progression in human patients. Furthermore, targeted
MMIC ablation through ABCB5 inhibits tumor initiation and
growth in preclinical xenotransplantation models, pointing
to potential therapeutic promise of the CSC concept. Recent
advances also show that CSCs can exert pro-angiogenic roles
in tumor growth and serve immunomodulatory functions related
to the evasion of host anti-tumor immunity. Thus, MMICs might
initiate and sustain tumorigenic growth not only as a result
of CSC-intrinsic self-renewal, differentiation and proliferative
capacity, but also based on pro-tumorigenic interactions with
the host environment.
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Article]
Novel Therapies Against Aggressive and Recurrent Epithelial
Cancers by Molecular Targeting Tumor- and Metastasis-Initiating
Cells and Their Progenies
M. Mimeault and S.K. Batra
A growing body of experimental evidence has revealed that
the highly tumorigenic cancer stem/progenitor cells endowed
with stem cell-like properties might be responsible for initiation
and progression of numerous aggressive epithelial cancers
into locally invasive, metastatic and incurable disease states.
The malignant transformation of tissue-resident adult stem/progenitor
cells or their progenies into tumorigenic and migrating cancer
stem/progenitor cells and their resistance to current cancer
therapies have been associated with their high expression
levels of specific oncogenic products and drug resistance-associated
molecules. In this regard, we describe the tumorigenic cascades
that are frequently activated in cancer stem/progenitor cells
versus their differentiated progenies during the early and
late stages of the epithelial cancer progression. The emphasis
is on the growth factor signaling pathways involved in the
malignant behavior of prostate and pancreatic cancer stem/progenitor
cells and their progenies. Of clinical interest, the potential
molecular therapeutic targets to eradicate the tumor- and
metastasis-initiating cells and their progenies and develop
new effective combination therapies against locally advanced
and metastatic epithelial cancers are also described.
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Article]
Potential Targets for Improving Radiosensitivity of
Breast Tumor-Initiating Cells
W. Xu, B.G. Debeb, L. Lacerda and W.A.
Woodward
Recent studies have suggested that a specific small population
of cells termed tumor-initiating cells (TICs) may be intrinsically
resistant to therapy including radiation, and may therefore
be the primary mediators of recurrence. Numerous targets are
being explored using multiple approaches for their involvement
in the self-renewal or survival as well as radioresistance
of breast TICs. These studies will provide a broad range of
compounds to be tested and to develop novel TIC radiosensitizers
that will improve clinical outcome and decrease recurrence
of cancer after radiation. In this review we will discuss
recent efforts to identify and target these cells to selectively
radiosensitize them with novel agents, as well as the TIC
radiosensitizing potential of current therapies already in
clinical use.
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Article]
Targeting Ovarian Cancer-Initiating Cells
S.K. Murphy
Evidence supports that a variety of cancers are sparked by
the growth of cells that exhibit characteristics of stem cells.
Such cancer-initiating cells are capable of populating a tumor
with a heterogeneous group of daughter cells while still maintaining
the ability to self-renew. Several groups have recently reported
the identification of cancer-initiating cells in ovarian cancer,
the most lethal gynecologic malignancy. Epithelial ovarian
cancer comprises 90% of cancers of the ovary and consists
of four major histologic types, each bearing some resemblance
to different tissues in the peritoneal cavity. Although epithelial
ovarian cancer has traditionally been thought to originate
from the single layer of cells surrounding each ovary, new
findings suggest that many of these cancers derive from Müllerian
epithelium. This raises questions about the origin of ovarian
cancer-initiating cells, and if there may be more than one
source. Despite the initial effectiveness of primary therapy
against advanced stage ovarian cancer, most of these cases
recur, months to years following diagnosis. The cause of disease
recurrence is unknown, but may involve cancer-initiating cells
that survive chemotherapy and enter a period of dormancy while
residing in as-yet undefined niches within the body before
being triggered to initiate renewed growth. Herein the nature
of these cells is explored as well as novel approaches for
therapeutic targeting.
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Lung Cancer Stem Cells as a Target for Therapy
E. Gorelik, A. Lokshin and V. Levina
Despite significant efforts in diagnosing and treating lung
cancer, therapeutic resistance remains a major unresolved
clinical and scientific problem. Cancer stem cells (CSCs)
are thought to be responsible for the failure of current chemotherapy
of lung cancer. The concept of CSCs has radically changed
the view of cancer therapy. Today a majority of current treatment
modalities target the differentiated cancer cells and avoid
the drug resistant cancer-initiating stem cells. This review
summarizes our understanding of lung CSCs and their role in
metastasis formation and growth of non- small-cells lung cancer
(NSCLC). High tumorigenic and metastatic properties of lung
CSCs are associated with the efficient cytokine network production
and with the specific signaling pathways. This review underlines
the experimental evidence indicating that the stem cell factor
(SCF) and its receptor c-kit (CD117) play an important role
in survival and proliferation of lung CSCs. Thus, molecularly
targeting key cytokine network axes of such highly tumorigenic
and metastatic CSCs must be considered for improving the current
anti-cancer strategy efficacy. Standard chemotherapy in combination
with specific axis of cytokine network targeting, such as
SCF-c-kit, could eliminate both bulk tumor cells and CSCs,
and therefore to be truly curative thera-pies. This review
provides a summary of some of the developments in the field
of lung CSCs targeting and highlights aspects which could
help in the drug discovery process.
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Liver Cancer Stem Cells as an Important Target in
Liver Cancer Therapies
G.-M. Zou
Hepatic cancer is one of most common cause of cancer-related
death. Hepato-epithelial cancers are believed to originate
from the malignant transformation of liver-resident stem/progenitor
cells. Liver cancer stem cells have been characterized recently
and the phenotype of liver cancer stem cells has been defined
as CD133+ CD44+
cancer cells. Recently, it has been also demonstrated about
the relevance of targeting liver cancer stem cells, due to
cancer stem cells are related to cancer metastasis. These
advances no doubt to bring the new strategy in liver cancer
treatment and control in this disease. This review describes
the current status and progress about cancer stem cell research
in liver and discuss of the implications of these studies
in new liver cancer treatment strategies.
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Article]
Gestational Trophoblastic Neoplasia, an Ancient Disease:
New Light and Potential Therapeutic Targets
M. Alazzam, J. Tidy, B.W. Hancock and H.J. Powers
Gestational trophoblastic neoplasia is a rare malignancy,
which can occur after any type of pregnancy. The incidence
varies according to the geographical location and ethnic origin.
Although most patients with gestational trophoblastic neoplasia
are cured by conventional chemotherapy and surgery, some suffer
resistant disease and may die. New therapeutic agents are
needed to reduce the toxicity associated with conventional
chemotherapy and treat those with resistant or refractory
disease. Molecular targeted treatment provides an exciting
avenue; however, the biology of gestational trophoblastic
neoplasia is not well understood. This review briefly summarises
recent advances in the understanding of the pathogenesis and
molecular biology of this group of diseases and sheds light
on molecules that could provide potential therapeutic targets.
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