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Introduction
It is increasingly clear that all biological processes, in
principal, rely on chemical processes that are governed by
the structure of the participating molecules and their
interactions and, thus, the biological processes can be treated as
chemical processes and studied in molecular detail. The
Human Genome Program was a landmark event for life
science and has uncovered a large number of novel genes and
provided an unprecedented prospectus for target
identification and the development of drugs. However, the function
of these genes cannot be predicted merely from their
structure, thereby demonstrating the need for the
systematic collection of biological information in addition to the
gene sequence to fully exploit the genomic data. As a result,
the accumulation of genome sequence data has not resulted
in the anticipated acceleration of novel therapeutic
develop-ments. We are now facing the exciting but daunting task of
identifying and assigning functions and therapeutic
potentials to all 30 000 human genes[1]. To address the latter issue,
a myriad of strategies have emerged to facilitate
genomics-driven target identification and validation. The "functional
genomics" technologies, such as genetic-based knock-out
and knock-in, RNAi and ectopic expression of targeted genes,
high-throughput cellular profiling of gene and protein
expression, systematic analyses of protein complexes and
bioinformatics, have played active roles in the past few years.
Many of these techniques are used in limited classes of gene
products, but none of the techniques has proven to be the
generally useful strategy that was
anticipated[1,2].
Small molecules participate directly in many biological
processes and function in diverse roles, including chemical
triggers, inhibitors, stimulators and switches. In contrast,
compared with genetic approaches, the effect of small
molecules is generally fast and reversible because of the
metabolism and excretion of the molecules, which enables
transient study of the proteins. In addition, the effect of small
molecules is tunable because a varying concentration can
result in different degrees of phenotype
expression[3]. Therefore, small active molecules, providing a common link
between the fields of chemistry and biology, have long had
an important role in deciphering answers to fundamental
biological questions, especially in the exploration of signaling
networks for cellular activities. In the past decade, chemical
biology, aimed at studying signaling networks for basic
cellular activities using specific, active small molecules as
probes, has developed rapidly. This rise in chemical biology
greatly accelerates research on molecular mechanisms and
target therapy of diseases, especially in malignant tumors.
Complementary to genetics and genomics, chemical biology
has become an effective tool to study the functions of
proteins/genes and important cellular
activities[1,4,5]. The recent explosion of interest in chemical biology combined with
genetic manipulation reflects a fascination with research at
the interface of chemistry and biology, where chemical
insights are brought to bear on exciting biological and
biomedical problems[6].
Leukemia, a heterogeneous group of hematopoietic
malignancies that occurs worldwide, includes acute/chronic and
myeloid/lymphocytic leukemias. Despite many important
advances in understanding the biological, molecular and
cytogenetic aspects of leukemia, as well as in the diagnosis
and therapy of leukemia, the most people will die of their
diseases[7,8]. Obviously, it is imperative to understand the
pathophysiological mechanisms of leukemia and to explore
new therapeutic strategies. It has been widely understood
that various kinds of leukemias present specific cytogenetic
alterations, especially chromosome translocations, that
generate abnormal oncogenic fusion
proteins[9]. These alterations disrupt the normal signaling and cause uncontrolled
proliferation, blocked differentiation and/or damaged
apoptosis. Because of these genetic and cellular features,
and because of the ease of capture of leukemia samples and
the relatively convenient evaluation of therapeutic effects,
small molecule-based chemical biology has been widely used
with leukemia and important progress has been achieved
over the past two decades. Based on several examples, mainly
from our own work, this review will outline the advances of
chemical biology in understanding molecular mechanisms
of cell differentiation and apoptosis induction and target
therapy of leukemia.
All-trans retinoic acid-based chemical biology
of leukemia
An important feature of acute myeloid leukemia (AML),
which accounts for 75% of all acute leukemias, is the
blockage of the differentiation of myeloid cells at different stages.
Over the past 20 years, many studies have explored the
differentiation-inducing agents for leukemic cells. A typical
and successful example is the discovery of
all-trans retinoic acid (ATRA) as a differentiation-inducing drug for acute
promyelocytic leukemia (APL)[10], a unique subtype of AML
that is defined by blockage at the promyelocytic stage of
myeloid cell maturation. Using cytogenetic analysis, it has
been shown that over 95% of patients with APL carry
specific chromosome translocation t(15,17), which leads to the
fusion of the promyelocytic leukemia (PML) gene on
chromosome 15 and the retinoic acid receptor-alpha
(RARα) gene on chromosome 17, and the generation of
PML-RARα
fusion protein[11]. A series of in
vitro and in vivo works, including those from transgenic
mice[12], have shown that this fusion protein plays a critical role in the pathogenesis of
APL via interfering functions of wild-type PML,
RARα and its heterodimeric partner retinoid X receptor (RXR), as well
as obtaining its new functions, as widely
reviewed[13_15]. As widely confirmed, ATRA can induce complete clinical
remission, although retinoid resistance and relapse frequently
occur[16]. Because ATRA can cleave the
PML-RARα fusion protein and, more importantly, it can potently drive AML
cells to undergo differentiation, ATRA as a probe has greatly
promoted our understanding of signaling pathways of
leukemogenesis and leukemic cell differentiation. Using
chemical and biological studies based on ATRA and other
differentiation-inducing agents, such as phorbol 12-myristate
13-acetate (PMA) and vitamin D3, many differentiation and
leukemogenesis-related molecules, such as CCAAT/enhancer
binding protein (C/EBP), nuclear corepressors (N-CoR), Sin3A
and histone deacetylase (HDAC), have been
examined[17,18]. Vice versa, knowledge of these differentiation-related
molecules has also led to the development of new
differentiation agents, such as HDAC inhibitor valproic
acid[19].
As an example, phospholipid scramblase 1 (PLSCR1) is a
multiply palmitoylated protein that is localized in either the
cell membrane or nucleus depending on its palmitoylated
state. Increasing evidence has demonstrated the biological
role of PLSCR1 in cell signaling, maturation and apopto-
sis[20]. ATRA can elevate PLSCR1 expression in
ATRA-sensitive APL cells NB4 and HL60, but not in maturation-
resistant NB4-LR1 cells. Furthermore, PMA, but not
dimethyl sulfoxide (DMSO), sodium butyrate or
vitamin-D3-induced leukemic cell differentiation, is also accompanied
by increased PLSCR1 protein[20] . Based on the fact that
ATRA and PMA can activate protein kinase Cdelta
(PKCd) by phosphoryla-tion, PKCd-specific inhibitor rottlerin
is shown to nearly eliminate ATRA-induced and PMA-induced
PLSCR1 expression, whereas ectopic expression of a
constitutively active form of PKCd directly increases PLSCR1
expression[21]. Thus, PKCd is proposed to exert a critical role
in ATRA-induced or PMA-induced PLSCR1 expression.
Furthermore, interferon upregulates PLSCR1 by sequential
activation of PKCd, JNK and STAT1[22]. In contrast,
decreasing PLSCR1 expression with small interfering RNA (siRNA)
inhibits ATRA/PMA-induced
differentiation[21], whereas inducible PLSCR1 expression induces growth arrest at the
G1 phase and granulocyte-like differentiation together with
increased sensitivity to apoptosis
induction[23]. All these data support the anti-leukemia role of PLSCR1, although its exact
molecular mechanisms need to be further investigated. In
agreement with this notion, M2, M5a, and M5b type AML
cells present lower levels of PLSCR1 than normal bone
marrow cells, and the PLSCR1 mRNA level is associated with
significantly longer overall
survival[24].
Arsenic trioxide-based chemical biology of leukemia
Following the successful practice of ATRA, several
research groups in China, including ours, reported
impressive clinical response rates in patients with APL who had
received arsenic trioxide
(As2O3), a common naturally
occurring substance. Subsequently, clinical studies conducted in
other nations confirmed earlier reports and
As2O3, commercial name Trisenox (Cell Therapeutics, Seattle, WA, USA),
was approved by the Food and Drug Administration for the
treatment of relapsed/refractory
APL[25_32]. Later, single-agent
As2O3-induced durable remission with minimal
toxicity in the newly diagnosed APL was also
reported[33_35]. Following these successful experiences, the mechanisms of
As2O3 action on APL cells and other cancer cells have been
attracting wide interest and great progress has been
made[36_38]. In brief,
As2O3 can rapidly modulate the
subcellular localization of PML and PML-RARα proteins and
degrade PML-RARα protein[39_41]. In a cytological direction,
As2O3 induces apoptosis in an impressive array of cancer
cells in addition to APL[42], in which various kinds of
mechanisms have been documented[43,44]. However, the clinical
effectiveness of As2O3 appears to be restricted to APL,
although clinical studies have shown that
As2O3-based regimens are clinically active in patients with
relapsed/refractory multiple myeloma
(MM)[45]. In contrast, in vivo
observations in APL patients and animal models show that
As2O3 can induce partial differentiation of APL
cells[27,41,46]. Hence, the in
vitro differentiation-inducing effect of
As2O3 was
investigated in APL cells. Indeed, a relatively longer
treatment of low-dose As2O3 (0.1_0.5 µmol/L) induces APL cells
to undergo partial
differentiation[41,47]. However, it appears
that it is not more significant than its in
vivo activity. Thus, we speculated that some factors in the bone marrow (BM)
microenvironment could modulate the in vivo activity of
As2O3. Towards this end, we considered that oxygen
concentration may be one such factor that impinges on the
in vivo action of
As2O3 based on the following facts: leukemic
cells are cultured in vitro at ambient oxygen, whereas
in vivo cells are physiologically exposed to much lower oxygen
levels ranging from 16% in pulmonary alveoli to less than 6% in
most peripheral organs of the body. Oxygen levels of BM in
AML patients may be decreased as a result of the fast growth
of leukemic cells, and are possibly further aggravated by the
anemia that often accompanies newly diagnosed AML patients, although leukemic cells do not form
a well-circumscribed "mass" in BM like they do in solid tumors. More
importantly, angiogenesis, which increases blood supply and
oxygen tension, is also vital in the pathogenesis of different
hematologic malignancies and provides an independent
predictor of outcome in adults with AML, while the
anti-angiogenic effects of chemotherapeutic and other novel drugs for
the treatment of leukemia, such as ATRA and
As2O3, might contribute to their therapeutic potentials. We investigated
whether low oxygen tension impacts on the action of
As2O3 on APL cells. Unexpectedly, cobalt chloride
(CoCl2)/desfer-rioxamine (DFO)-mimicked hypoxia or moderate hypoxia (2%
and 3% O2) can directly trigger AML cells to undergo
differentiation both in vitro and in
vivo[48_50]. The differentiation-inducing effect of
As2O3 on APL cells is also enhanced by
hypoxia mimetic agents[51]. Using chemical interference,
inducible expression and siRNA technology, it is confirmed
that hypoxia-inducible factor (HIF)1α exerts a critical role in
this event, possibly in a transcription activity independent
manner[49,52]. Furthermore, HIF-1α interacts with and
increases the transcription activities of two known
hematopoiesis transcription factors, AML1 and CCAAT/enhancer
binding factor-alpha (C/EBPα)[49,53-55]. A low concentration
of Tiron, a non-toxic chelator used to alleviate acute metal
overload, has recently been shown to be a potent inducer of
cell differentiation in human promyelotic HL-60 leukemia cells
via increased HIF-1α and C/EBPα[56]. Intriguingly,
HIF-1α is dysregulated in a murine APL
model[57]. Nguyen-Khac also recently reported that hypoxia accelerates the
differentiation of normal CD34+ cells, whereas TEL-ARNT fusion
protein, which results from t(1;12)(q21;p13), inhibits
hypoxia-induced normal progenitor cell differentiation through the
interaction of TEL-ARNT with HIF-1α[58,59].
Apoptosis induction-based chemical biology of
leukemia
As an intrinsic cell death program, apoptosis plays a
critical role in the tissue homeostasis of multicellular organisms,
especially in organs, such as the hematopoietic system, where
high rates of daily cell production are offset by rapid cell
turnover. Indeed, the hematopoietic system provides
numer-ous examples to show the importance of apoptotic cell death
for achieving the control of homeostasis. Correspond-ingly,
disorder of the apoptosis machinery would cause various
diseases. For example, damaged apoptosis exerts an
important role in the pathogenesis and resistance to
chemotherapeutic drugs of cancers including
leukemia[60]. Therefore, to understand the core molecular mechanisms of the apoptosis
machinery has become an important and interesting research
direction.
Over the past years, much progress has been achieved
in understanding the molecular mechanisms of initiation and
regulation of apoptosis. In brief, apoptosis is mainly caused
by the activation of intracellular aspartate-specific proteases,
known as caspases, with over 10 members (eg, caspase-8, 9
and 3). The mechanisms of caspase activation by apoptosis
inducers have been the center of much attention in recent
years. To date, two pathways of caspase activation and,
thus, apoptosis have been elucidated in great detail, that is,
the mitochondria-centered intrinsic and death
receptor-mediated extrinsic pathways. As for the former, multiple
signals cause dysfunction of mitochondria, especially disrupted
mitochondrial transmembrane potentials, which leads to the
release of apoptogenic proteins, such as cytochrome c,
second mitochondrial activator of caspase (Smac) and
apoptosis-inducing factor (AIF), into the cytosol. Cytochrome c binds
the apoptotic protease-activating factor 1 (Apaf1) and forms
the apoptosome together with procaspase-9. In this
multiprotein structure, caspase-9 is activated and then
activated caspase-9 activates downstream effector caspases,
mainly procaspase-3. In the extrinsic apoptotic pathway,
death receptors such as Fas, containing a cytosolic death
domain (DD), cluster in membranes when they bind to their
ligands, which recruits caspase-binding adaptor proteins,
such as the Fas-associating protein with death domain
(FADD) that contains both a death domain (DD) and a death
effector domain (DED). The DED of FADD binds
DED-containing procaspases (eg caspase-8 and caspase-10), forming
a death-inducing signaling complex (DISC) and resulting in
downstream effector caspase-3. The activated caspase-3
cleaves numerous cellular target proteins, which in
aggregate produce an apoptosis-characteristic morphology and
biochemical alterations. In contrast, apoptosis machinery is
also regulated by many proteins, including bcl-2 family
members, inhibitors of caspases, oncoproteins and
tumor-suppressing protein, and other signaling molecules. Thus, a
delicate balance between pro-apoptotic and anti-apoptotic
regulators of apoptosis pathways is essential to ensure the
survival of long-lived cells and the proper turnover of
short-lived cells in a variety of tissues.
During these great advances on apoptosis, chemical
approaches with small-molecule apoptosis inducers and
inhibitors as probes provided a huge help. In fact, a lot of
information on cell apoptotic processes was contributed by
chemical biological investigations[61]. For example, wild p53
was found to actively mediate the apoptosis of the
hematopoietic cells by depriving the cells of specific growth factors,
such as IL-3, and p53 might be involved in the response of
myeloid precursors to environmental cytokines for the
maintenance of hematopoietic
homeostasis[62]. Recently, we
reported that nanomolar concentrations of NSC606985, a
rarely studied camptothecin analog, induces apoptosis in
AML cells through the rapid proteolytic activation of
PKCd, followed by the loss of mitochondrial transmembrane
potential and caspase-3 activation[63]. Furthermore, the potential
therapeutic effect of this agent on AML mice generated by
syngenic grafts of leukemic blasts from transgenic mice with
PML-RARα was also shown[64]. Moreover, inducible
expression of AML1-ETO, a fusion gene of the AML1 gene
on chromosome 21 with the ETO (eight-twenty-one) gene
on chromosome 8, endows leukemic cells with susceptibility
to NSC606985 and other insult-induced
apoptosis[65]. Using subcellular and quantitative proteomic analyses, moreover,
we found a set of unique deregulated proteins in
NSC606985-induced apoptotic AML cell line NB4 cells, including 16
compartment-compartment translocated ones. These proteins
contributed to multiple functional activities, such as DNA
damage repair, chromosome assembly, mRNA processing,
biosynthesis, modification and degradation of proteins
(Figure 1)[66]. These discoveries shed new insights for
systematically understanding the mechanisms of
camptothecin-induced apoptosis.
In contrast, the application of chemical biology in
understanding the core components of the apoptosis machinery
at the molecular and structural levels aids the discovery of
many new potential therapies for leukemia, as reviewed by
Reed and Pellecchia[67]. For instance, Bcl-2 family was
recently raised up as the drug target for leukemia. The
common aberrant expression of Bcl-2 in chronic lymphocytic
leukemia (CLL) was proposed to confer CLL B-cell the unusual
feature of resistance to undergoing apoptosis and dying
properly, which is associated with leukemogenesis, poor
response to chemotherapy and decreased overall survival of
CLL. Consequently, selective apoptosis induction of
malignant cells by interfering Bcl-2 is growing as a potential basic
therapeutic strategy. In the past years, various apoptosis
inducing and regulating drugs or lead compounds,
including anti-apoptotic Bcl-2 or Bcl-XL
expression regulating drugs (such as synthetic retinoic acid and inhibitor of histone
deacetylase) and drugs directly binding to Bcl-2 or other
anti-apoptosis proteins (such as Gossypol isolated from
cottonseed, HA14-1, BH3I-1, and BH3I-2, GX15-070) have
been discovered.
AML cells are also characterized by constitutive and
abnormal activation of the nuclear factor-kappaB
(NF-κB) transcription factor. In addition, NF-κB also plays a crucial
role in the pathogenesis, survival and resistance to apoptosis
of HTLV-I-infected leukemic cells[68], B-cell chronic
lymphocytic leukemia (B-CLL)[69], which is also supported by the
fact that the PML can enhance the sensitivity of
TNF-α induced apoptosis through the repression of the
NF-κB survival pathway[70], while transfection of a dominant-negative
mutant NF-κB inhibitor represses p53-dependent apoptosis
in acute lymphoblastic leukemia cells
(ATL)[71]. Taken together, NF-κB is a suitable target for the prevention and
treatment of ATL[68]. Interestingly, a specific
pharmacological inhibitor of AS602868 could block
NF-κB activation and lead to apoptosis of human primary AML cells. Moreover,
AS602868 potentiated the apoptotic response induced by
the current chemotherapeutic drugs doxorubicin, cytarabine
and etoposide (VP16). In addition, NF-κB inhibition did not
affect normal CD34+ hematopoietic precursors, suggesting
that it could represent a new adjuvant strategy for AML
treatment[72]. At the same time, indole-3-carbinol, found in
brassica species vegetables (such as cabbage, cauliflower
and brussels spouts), can inhibit NF-κB and
NF-κB-regulated gene expression and this mechanism may provide the
molecular basis for its ability to suppress
tumorigenesis and clinical
application[73].
Leukemogenic fusion proteins-based chemi-cal biology
Different types of leukemia usually have specific
chromosome translocations that cause the activation of
onco-genes and, in particular, the formation of abnormal fusion
genes, such as AML1-ETO[74_76], a fusion protein generated
by t(8,21) translocation that occurs in approximately 12% of
all AML and 40% of M2-type AML. These fusion proteins
play a pivotal role in leukemogenesis. Thus, using some
small molecules to destroy them or to inhibit their activities
may become an effective method to treat the corresponding
type of leukemia, while these active small molecules would
be more useful for understanding leukemogenic mechanisms
of these fusion proteins. The destruction of
PML-RARα by ATRA and As2O3 is a good model. Another typical example
is the discovery of Bcr-Abl kinase inhibitor imatinib mesylate
(also called Gleevec, STI571)[77]. Bcr-Abl is a constitutively
active, cytoplasmic tyrosine kinase that is produced by
t(9;22) translocation in more than 95% of chronic myelogenous
leukemia (CML) and about half of patients with adult-onset
acute lymphoblastic leukemia (ALL). The central role of
Bcr-Abl kinase in leukemogenesis promoted it as an ideal target
for drug screen to treat CML. Hence, imatinib was
discovered as a tyrosine kinase inhibitor and was introduced into
the armamentarium of drugs for the treatment of CML and
has since revolutionized its
management[77]. Imatinib has a high affinity for the ATP-binding site of Abl, and clinical
trials have validated the promise of this molecular targeted
therapy. In the more advanced phases of CML, imatinib was
able to induce a major (complete or partial) cytogenetic
response in 16%_60% of CML patients. In a phase III trial
comparing imatinib with interferon-α plus cytosine
arabinoside in newly diagnosed chronic phase CML, 85% of
patients treated with imatinib attained a major cytogenetic
response after a median follow-up of 19 months, compared
to 22% in patients treated with the latter combination. A
recent update has shown a further increase in major
cytogenetic response of up to 92% of patients in the imatinib arm
after a median follow-up of 54 months. In view of its high
efficacy and low toxicity, imatinib has now replaced
interferon-α as the frontline treatment for CML patients who are
not eligible for allogeneic stem cell transplantation.
Meanwhile, the application of imatinib as a probe greatly
improved our understanding of Bcr-Abl-targeted signaling
pathways, and has revealed a complex web of signals that
promote cell division and survival[78].
Imatinib is now frontline therapy for CML, but resistance
is increasingly encountered, which has dampened the initial
enthusiasm for this much heralded "magic bullet". It has
been shown that resistance to imatinib in CML occurs
through the selection of tumor cells harboring Bcr-Abl
kinase domain point mutations that interfere with drug
binding. To date, at least 73 different point mutations
leading to the substitution of 50 amino acid residues in the Abl
kinase domain have been isolated from CML patients
resistant to imatinib. Crystallographic studies revealed that
imatinib binds to the ATP-binding site of Abl only when the
activation loop of the kinase is closed and stabilizes the
protein in this inactive conformation. Thus, most
imatinib-resistant mutants should remain sensitive to inhibitors that
bind Abl with less stringent conformational requirements.
Based on this notion, an orally bioavailable Abl kinase
inhibitor called Dasatinib (BMS-354825) has been examined[79], which presents a two-log increased potency relative
to imatinib that retains activity against 14 of 15
imatinib-resistant Bcr-Abl mutants. Clinical trials of Dasatinib in
imatinib-resistant and imatinib-intolerant CML and Ph
chromosome-positive ALL are currently in
progress[80_82].
Conclusion
The rapid rise of chemical approaches, that is, studying
signaling networks using basic cell activities with specific,
active small molecules as probes, greatly accelerates research
on the molecular mechanisms of disease and target therapy,
especially in malignant tumors such as leukemia. With the
application of chemical approaches combined with genetic
manipulation, significant progress on the basic knowledge,
diagnosis and therapy of leukemia has been achieved over
the past few decades. In particular, discoveries of the
clinical effectiveness of ATRA and
As2O3 in the treatment of APL
and of Bcr-Abl kinase inhibitor Imatinib and Dasatinib in the
treatment of CML not only make target therapy of leukemia a
reality, but also push mechanisms of leukemogenesis and
leukemic cell activities forward. These successful practices
are attracting wide interest on the application of a chemical
approach in leukemia and other cancers.
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