|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
REVIEW ARTICLE
From the INSERM E9910, Institut Claudius Régaud,
Toulouse, France; and the Service d'Hématologie, Centre
Hospitalier Universitaire Purpan, Toulouse, France.
The anthracycline daunorubicin is widely used in the
treatment of acute nonlymphocytic leukemia. The drug has, of course, been the object of intense basic research, as well as preclinical and
clinical study. As reviewed in this article, evidence stemming from
this research clearly demonstrates that cell response to daunorubicin
is highly regulated by multiple signaling events, including a
sphingomyelinase-initiated sphingomyelin-ceramide pathway,
mitogen-activated kinase and stress-activated protein/c-Jun N-terminal
kinase activation, transcription factors such as nuclear factor The anthracycline daunorubicin (DNR) is one
of the major antitumor agents widely used in the treatment of acute
myeloid leukemias (AMLs). Cytotoxicity mediated by DNR is generally
thought to be the result of drug-induced damage to DNA. This damage is
mediated by quinone-generated redox activity, intercalation-induced
distortion of the double helix, or stabilization of the cleavable
complex formed between DNA and topoisomerase II.1 However,
how and why such events should bring about cell death remains unclear, especially when one considers that DNA interaction may not be a
prerequisite for anthracycline cytotoxicity.2-5 Hence, the exploration and understanding of the process of apoptosis has forced a
reconsideration of the mechanisms whereby myeloid leukemia cells
respond to DNR. In this context, we have shown that, within a narrow
concentration range (0.2-1 µM), DNR can trigger apoptosis in the
monocytic U937 or the myelocytic HL-60 AML cells but not in the
immature (CD 34+) KG1a, KG1, or HEL cells,6
the latter being more resistant to DNR than the former.7
These results suggested that DNR triggers apoptotic signals in
drug-sensitive AML cells and that inhibition of these signals may
contribute to drug resistance and, for example, to the inherent
resistance of immature AML cells. For this reason, others and we have
investigated the mechanism by which DNR activates apoptosis in
DNR-sensitive AML cells.
DNR activates the sphingomyelin cycle in sensitive
leukemic cells
On the basis of those studies, our group investigated the role of the
sphingomyelin-CER pathway in DNR-induced apoptosis. DNR exposure at
concentrations that induced apoptosis (0.5-1 µM) stimulated early
(5-10 minutes) sphingomyelin cycle (hydrolysis and resynthesis) and
subsequent CER generation in both U937 and HL-60 cells. The
concentration of endogenous CER generated (~10 µM, estimated by
cell volume) is clearly sufficient to induce apoptosis.8
Because these cells exhibit a mutated or deleted form of p53, it
appears that CER operated through a p53-independant mechanism. Further
studies have shown that DNR induced sphingomyelin hydrolysis associated
with the stimulation of N-SMase, whereas acidic SMase did not appear to
be involved.10 Moreover, we have recently reported that
DNR induced sphingomyelin cycle, CER generation, and apoptosis in
Epstein-Barr virus-transformed lymphoblastoid cell lines established
from patients with Niemann-Pick disease, a genetic disorder
characterized by the lack of acidic SMase activity.11 These results suggest that acidic SMase is dispensable for DNR-induced sphingomyelin hydrolysis.
In another study, Bose et al12 have proposed that DNR may
induce CER accumulation because of enhanced de novo synthesis through
CER synthase stimulation, a mechanism that has also been suggested for
TNF In this study, we have found that DNR exposure resulted in at least 4 sphingomyelin cycles (hydrolysis and resynthesis) with concomitant (4 cycles) CER production within the first 4 hours, after which
poly(ADP-ribose) polymerase cleavage, DNA laddering, and
apoptosis-associated morphologic changes occurred. Moreover, the
successive waves of CER production were not influenced by fumonisin B1,
a potent and specific CER synthase inhibitor.15 These
results confirmed that de novo CER synthase plays little if any role in
DNR-induced CER signaling. The fact that DNR induced several peaks of
CER production suggested that sphingomyelin hydrolysis products (ie,
CER or phosphorylcholine) might reactivate N-SMase. In fact, we have
found that cell-permeant CER may indeed stimulate N-SMase,
sphingomyelin hydrolysis, and endogenous CER production, suggesting
that CER may enhance its own production through feedback control of
N-SMase.15 Therefore, one can speculate that DNR activates
a single sphingomyelin cycle that is sufficient for inducing CER
autoproduction and that these repeated CER-mediated apoptotic signals
are perhaps needed for maintaining an apoptotic (cell suicide)
signaling pressure overcoming latent cell survival mechanisms. Finally,
it is noteworthy that DNR-induced topoisomerase II cleavable complexes
have not been described in the literature under these conditions (1 µM DNR treatment for 4 hours); of course this does not demonstrate
unambiguously that DNR interaction with DNA, or more specifically with
topoisomerase II, is not requisite for apoptosis signaling because it
can be argued that present experimental procedures lack sensitivity in
detecting minute amounts of DNR-topoisomerase-DNA complexes.
CER targets
Regulation of CER production CER production is limited by both N-SMase activity and the magnitude of sphingomyelin pool disposable for hydrolysis. Previous studies have shown that N-SMase activity is strongly influenced by protein kinase C (PKC) activity. For example, we have reported that phorbol ester- or phosphatidylserine-induced PKC stimulation resulted in the inhibition of N-SMase stimulation, sphingomyelin hydrolysis, CER production, and apoptosis induced by DNR in U937 cells.32 Conversely, PKC inhibitors were found to stimulate N-SMase.33 The amount of hydrolyzable sphingomyelin is another candidate for regulating CER production. Indeed, it has been reported that, whereas sphingomyelin is preferentially distributed within the outer leaflet of the plasma membrane (sphingomyelin transverse asymmetry), the sphingomyelin pool disposable for hydrolysis consists primarily in the sphingomyelin component that is associated to the plasma membrane inner leaflet.34 Thus, it is conceivable that reduction of hydrolyzable sphingomyelin pool because of altered transverse asymmetry may result in reduced CER production. In 2 studies, we have reported that, in KG1a AML cells, which are naturally resistant to DNR,7 mitoxantrone,35 and TNF ,36 the inner leaflet-associated sphingomyelin
pool was greatly reduced, compared with the sensitive U937 cells,
whereas KG1a and U937 cells exhibited similar total sphingomyelin
amount. Interestingly, in the resistant cells, cytotoxic effectors such
as TNF,36 DNR, and mitoxantrone (A Bettaiëb et
al, unpublished results, July 1997) failed to induce
sphingomyelin hydrolysis, CER generation, and apoptosis. Thus, it is
possible that, in some AML cells, the activation of yet undefined
sphingomyelin translocases results not only in modification of
sphingomyelin transverse asymmetry but also in reduced sphingomyelin
hydrolyzable pool, decreased CER production, and inhibition of
apoptosis.37 Confirming this hypothesis, it has recently
been shown that the CER generated from the plasma membrane
sphingomyelin gains access to a SMase because of phospholipid
scrambling.38
Regulation of CER metabolism Intracellular CER concentration results from the equilibrium between CER production and CER metabolism. CER metabolism also plays an important role in regulating intracellular CER concentration and therefore DNR cytotoxicity. Theoretically, CER produced by DNR may enter into 3 distinct metabolic pathways that all result in decreasing intracellular CER levels.First, CER can be transferred to a phosphorylcholine group to generate sphingomyelin (and diacylglycerol [DAG]) on sphingomyelin synthase stimulation. It is likely that this metabolic pathway is activated for sphingomyelin resynthesis after sphingomyelin hydrolysis during the sphingomyelin cycle. This enzyme therefore has the important ability to directly regulate, in opposite directions, CER and DAG levels within the cells.39 However, despite the great biological potential of sphingomyelin synthase, very little is known about location, distribution, and regulation of this enzyme.40 Whether sphingomyelin synthase plays a role in DNR-induced cytotoxicity remains to be investigated. Second, on ceramidase stimulation, CER can be catabolized into sphingosine that, in turn, can be converted into sphingosine-1-phosphate through sphingosine-1-kinase. In a recent study, we have reported that DNR induced CER production and apoptosis in cells derived from Farber disease, which are genetically deficient for lysosomal ceramidase, the major component of cellular ceramidase activity.41 Although we cannot totally exclude the implication of extralysosomal ceramidases,42 this result suggests that sphingosine plays little if any role in DNR-induced apoptosis. However, from studies performed by Cuvillier et al,43,44 sphingosine-1-phosphate has emerged as one of the most potent regulators of apoptosis. Indeed, sphingosine-1-phosphate inhibits apoptosis induced by CER and other effectors.43,44 The mechanism by which sphingosine-1-phosphate interferes with CER-induced apoptotic signaling is not fully understood. However, it has been reported that sphingosine-1-phosphate inhibits CER-induced JNK stimulation and caspase activities.44,45 Therefore, sphingosine-1-phosphate and sphingosine-1-kinase might play an important role in regulating DNR-induced apoptosis. In fact, it has been demonstrated that sphingosine-1-phosphate inhibits doxorubicin-induced apoptosis.46 From these studies, one can speculate that sphingosine-1-kinase stimulation may contribute to DNR resistance. Because sphingosine-1-kinase is potently stimulated by PKC, it is possible that sphingosine-1-phosphate overproduction represents another mechanism by which PKC exerts its protective function in DNR-treated cells. Third, CER can be transformed to glucosylceramide by a glucosylceramide synthase. Previous reports have indicated that glucosylceramide has no cytotoxic property or may even stimulate cell proliferation47 and that glucosylceramide synthase inhibitors have been found to display some antitumor activity.48,49 These results suggest that glucosylceramide synthase plays an important role in cellular protection. Indeed, it has been described that cells transduced by glucosylceramide synthase gene were highly resistant to anthracyclines50 and that enzyme activity was significantly boosted in multidrug-resistant (MDR) cells.51 Conversely, transfection of glucosylceramide synthase antisense reverses adriamycin resistance.52 DNR triggers the sphingomyelin cycle in MDR cells when used at high doses.53 Therefore, one can speculate that in DNR-treated MDR cells CER originated from sphingomyelin hydrolysis is rapidly converted to glucosylceramide because of glucosylceramide synthase overactivity.54,55 If this speculation is the case, glucosylceramide synthase appears as an attractive target for MDR reversal. In fact, inhibition of CER glycosylation pathway increases MDR cell sensitivity to cytotoxics.56 The same group has reported that most MDR modulators, including cyclosporin A, tamoxifen, and verapamil, are potent glucosylceramide synthase inhibitors, whereas the cyclosporin A analogue PSC 833 (Valspodar), a clinically used potent MDR reversal agent, increases intracellular CER concentration by stimulating CER synthase.51,57,58 These results suggest that those agents may exert their chemosensitizing effect not only through their P-glycoprotein binding capacity, as previously postulated, but also by facilitating CER accumulation. However, the mechanism by which CER modulates anthracycline-induced cytotoxicity in MDR cells remains to be determined. For example, there is no evidence that CER interferes with P-glycoprotein function or intracellular drug distribution in MDR cells.59 Regulation of CER apoptotic signaling pathway The sphingomyelin-CER pathway appears to be efficiently regulated downstream of CER generation. Bcl-2 inhibits apoptosis induced by DNR without interfering with DNR-induced sphingomyelin cycle activation.60 This result is consistent with previous studies which have shown that Bcl-2 inhibits apoptosis induced by cell-permeant CER.61 PKC is also a potent regulator of CER-induced apoptosis. Indeed, previous studies not only showed that PKC activators, including phorbol esters and DAG, could inhibit the ability of cell-permeant CER to induce apoptosis but also that PKC inhibitors enhanced CER-induced apoptosis.9,32,62,63 Therefore, PKC appears as a critical regulator of the sphingomyelin-CER pathway because it operates both upstream and downstream of CER production. This finding may have important implications in our understanding of AML-cell drug resistance. Indeed, a large variety of hematopoietic growth factors (HGFs), including interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or basic fibroblast growth factor, were found to stimulate PKC activity through phosphatidylinositol or phosphatidylcholine hydrolysis and subsequent DAG production.64 Thus, it is conceivable that autocrine production of HGFs by leukemic cells may result in DNR-induced sphingomyelin-CER pathway inhibition and thereby contribute to reduce DNR cytotoxicity in AML. The fact that HGFs were found to inhibit DNR-induced apoptosis,65,66 as well as the chemosensitizing effect of PKC inhibitors on fresh AML cell progenitors cultured in the presence of HGFs,67 supports this hypothesis. Moreover, we have recently found that Kit signaling, activated either by its natural ligand (stem cell factor) or by modification of its intracellular domain, inhibits DNR-induced SMase stimulation, CER production, and apoptosis through a PKC-dependent mechanism.68
During the treatment of the cells with anthracyclines,
nicotinamide adenine dinucleotide phosphate (NADPH)-dependent flavin reductase reduces the drug to a semiquinone radical, which can donate
its free electron to molecular oxygen and generate the superoxide
radical (O Previous studies have shown that DNR-induced apoptosis was inhibited by
ROS scavengers such as pyrrolidine dithiocarbamate and N-acetylcystein,
a thiol antioxidant and a glutathione precursor, and was enhanced by
buthionine-sulfoximine, which depletes the glutathione
store.6 These results encouraged us to investigate the
role of ROS in the DNR-stimulated sphingomyelin-CER-JNK apoptotic pathway. Indeed, the level of endogenous H2O2
generated is comparable to that of a cell treated with 12 µM
H2O2. In fact, further studies showed that
pretreatment with N-acetylcystein abrogated DNR-induced N-SMase
stimulation, sphingomyelin hydrolysis, and CER generation induced by
DNR, evoking a role for ROS in N-SMase regulation.23 This
hypothesis is supported by 2 other studies which showed that H2O2 stimulates sphingomyelin hydrolysis and
CER generation and that N-acetylcystein and pyrrolidine dithiocarbamate
were potent inhibitors of TNF Other studies have demonstrated that ROS also plays a role in CER-induced apoptosis. Indeed, permeant CER induced early and transient (5-10 minutes) H2O2 production, followed by a second wave of H2O2 detected at 1 to 3 hours that originated from mitochondrial oxidative metabolism disturbances. Furthermore, N-acetylcystein inhibited H2O2 production, JNK activation, AP-1 activation, and apoptosis induced by CER.23,74,75 These results suggest that ROS plays an important role in the sphingomyelin-CER apoptotic pathway triggered by DNR at 2 different levels: upstream CER generation by stimulating N-SMase activity and downstream CER activity by mediating CER-induced JNK activation. The results also suggest a novel function of cytosolic-originated ROS in the cytotoxicity mechanism of anthracyclines. Thus, antioxidants, including superoxide dismutase, catalase, glutathione peroxidase, or thioredoxin, may influence DNR-induced cytotoxicity. However, the fact that antioxidants inhibit apoptosis induced by
chemotherapeutic drugs that have not been documented to stimulate the
sphingomyelin cycle (ie, actinomycin D, camptothecin, etoposide, and melphalan),76 raises the possibility that ROS
interferes with other apoptotic pathways in DNR-treated cells.
Furthermore, there is mounting evidence that ROS activates or mediates
many other signaling pathways, which can contribute more generally to
the cellular response to DNR. For example, ROS modulates both PKC77-79 and tyrosine kinase activities,80-85
contributes to cell cycle block,86 stimulates Raf-1/ERK
mitogen-activated protein (MAP) kinases,84,87 and triggers
activation of critical transcription factors, including nuclear
factor-
Anthracyclines, as other genotoxic agents including alkylating
agents and ionizing radiation, have been shown to increase cellular DAG
levels and PKC activity.90 However, the source of DAG as
well as its functional role in the cellular response to the drug were
not determined. In another study, we have reported that, in U937 cells,
DNR (and mitoxantrone) transiently stimulated concurrently with CER
generation both DAG and phosphorylcholine production by phospholipase C
hydrolysis of phosphatidylcholine. Moreover, pretreatment of cells with
the xanthogenate compound D609, a potent inhibitor of
phosphatidylcholine hydrolysis, led to a sustained increase in CER
levels. This result suggests that DNR may trigger in parallel both cell
death (CER) and survival (DAG and phosphorylcholine) mediators and
that, in sensitive leukemic cells, CER overrides the protective
function of DAG and phosphorylcholine.91 These results
support the notion that reciprocal regulation through DAG and CER may
be implicated in the regulation of apoptosis.92 The
mechanism by which phosphatidylcholine-derived DAG influenced intracellular CER concentration in DNR-treated cells is not yet characterized; however, because phosphatidylcholine-derived DAG did not
appear to influence N-SMase stimulation, it is conceivable that DAG
enhanced CER metabolism by facilitating sphingomyelin synthesis.
Furthermore, it has been documented that phosphatidylcholine-derived DAG binds and stimulates Raf-1 kinase activity93,94 and,
through Raf-1, may activate the MEK1/ERK classical MAP kinase module, a
negative regulator of apoptosis induced by various
stresses.84,87,95-97 Phosphatidylcholine-derived DAG has
been found to stimulate some PKC isoforms such as PKC
Among other enzymes that are involved in signal transduction
pathways, phosphoinositide 3-kinase (PI3K) plays an important role.
PI3Ks are a family of enzymes that catalyze the phosphorylation of
inositol lipids at the D3 position of the inositol ring, generating new
intracellular second messengers (see Franke et al105 for review). The lipid products of PI3K are
phosphatidylinositol-3-phosphate (PtdIns-3-P),
phosphatidylinositol-3,4-biphosphate (PtdIns-3,4-P2), and phosphatidylinositol-3,4,5-triphosphate
(PtdIns-3,4,5-P3). PtdIns-3,4-P2 and
PtdIns-3,4,5-P3 have been demonstrated to interact with a
large variety of downstream effectors, including serine-threonine kinase Akt,106 calcium-insensitive PKC
NF- Despite many efforts, the mechanism by which DNR activates NF- Previous studies have shown that NF- The mechanism by which NF-
Doxorubicin, as other antitumor compounds such as methotrexate, cisplatin, fludarabine, or bleomycin as well as ionizing radiation, was shown to enhance the expression of Fas and Fas-L on the surface of certain leukemic or epithelial malignant cells. For this reason, it has been proposed that doxorubicin-induced apoptosis occurs through autocrine or paracrine induction of the Fas-dependent pathway.148-151 In these studies, this hypothesis was supported by 2 lines of evidence: (1) cell lines resistant to Fas were found insensitive to anticancer drug-induced apoptosis, and (2) doxorubicin-induced apoptosis was prevented by CD95-neutralizing antibodies. However, this issue remains highly controversial mainly because antagonistic anti-Fas antibodies do not always inhibit drug-induced cell death.152-154 Moreover, many cells either naturally resistant to Fas (ie, HL-60 cells) or selected for Fas resistance152-154 remain sensitive to doxorubicin-induced apoptosis. Therefore, convincing evidence now exists showing that Fas/Fas-L pathway is not a principal and necessary mechanism of anthracycline-induced apoptosis.154 Other investigators have reported that in carcinoma cells doxorubicin
induced the clustering of Fas receptor and its interaction with
Fas-associated death domain-containing protein (FADD) in a
Fas-L-independent fashion.155 This has also been
described for UV and ionizing radiation.156,157 FADD is an
adapter molecule, which is recruited to Fas cell death domain, and then
binds to and activates procaspase-8; active caspase-8, in turn,
triggers activation of a proteolytic cascade that leads through
caspase-7, caspase-3, and caspase-6 to apoptosis. Moreover, these
investigators showed that FADD overexpression facilitated drug-induced
apoptosis, whereas down-regulation of FADD by transient transfection of
an antisense construct decreased tumor cell sensitivity to the
drug.155 For this reason, it has been proposed that
doxorubicin-induced cell death involves the Fas/FADD pathway without
interfering with Fas-L production and that FADD expression may
significantly influence the cellular response to this drug. Fas
clustering by cytotoxic agents was also described for VP-16,
cisplatinum, and vinblastin155 as well as for UV
radiation.157 However, the role of FADD in doxorubicin-induced caspase activation and apoptosis may be a function
of the cellular model. Indeed, in doxorubicin-treated Jurkat leukemic T
cells, Wesselborg et al154 have shown a correlation between doxorubicin-apoptosis and cleavage of procaspase-8 to its
active p18 subunit; however, the expression of a dominant-negative FADD
construct selectively abrogated Fas but not drug-induced effects. This
result suggests that caspase-8 can be activated by doxorubicin in the
absence of Fas receptor signaling.154 Fas- and
FADD-independent caspase-8 activation have been observed in lymphoid
cells treated with ionizing radiation.158 Altogether these
results suggest that, whatever the role of FADD, caspase-8 activation
represents a critical step in the cascade resulting in terminal
proteolytic events, including caspase-3 and caspase-6 activation
responsible for the cleavage of poly(ADP-ribose) polymerase and nuclear
lamins, respectively. However, other investigators have questioned the
role of caspase-8. For example, Villunger et al153 have
reported that expression of cowpox virus cytokine response modifier A,
a potent inhibitor of distinct members of the caspase-protease family,
including caspase-8,159 did not influence
doxorubicin-induced apoptosis in T-acute lymphatic leukemia CEM cells,
whereas it prevented Fas-mediated apoptosis. Moreover, expression of
FLIP (FLICE-inhibitory protein), which binds to caspase-8 and
interferes with its function, was found to have no influence on
apoptosis induced by doxorubicin or by other antileukemic compounds or
by Whatever the intimate mechanism by which Fas and caspases are involved in the cellular response to anthracyclines, all these results have important clinical implications. First, on the basis of the stimulatory effect of anthracyclines on Fas-L production in some tumor cells and with the demonstration that Fas-L produced by tumor cells can kill the specific effector CTL and other activated T cells that express Fas,164 it can be speculated that chemotherapy may decrease cellular cytotoxicity of natural effectors and, therefore, may facilitate immune escape.165 Conversely, it has been proposed that drug-induced Fas expression may result in sensitization toward Fas-dependent cytotoxicity of cellular immune effectors.166-169 Second, previous studies have shown that, whereas short-term culture with doxorubicin enhanced Fas expression level, prolonged exposure to the drug may result in Fas reduction or even lack of expression, establishing an intriguing link between MDR phenotype and Fas resistance.170 Similar results have been obtained with mitoxantrone.171 Third, if Fas signaling molecules (or Fas itself) play an important role in anthracycline-induced apoptosis, it is conceivable that diminution of their expression and/or altered capacity to form the multimolecular death-initiating signaling complex constituted by Fas death domain, FADD, and procaspase-8 may impair drug cytotoxicity. In this perspective, it is important to note that AML cells (as well as immature progenitor cells) are generally insensitive to Fas commitment although most of them do express Fas, suggesting a disruption in Fas-mediated death signaling.172-174 Therefore, it is tempting to speculate that negative control of Fas signaling contributes not only to immune escape but also to decreased drug cytotoxicity in leukemia cells. Finally, one should not disregard the emerging evidence that genotoxic stress, such as anthracycline treatment, has been described to increase death receptors such as DR5 for TRAIL/Apo-2 ligand in leukemia cells lines such as U937 and HL-60.175,176 These observations strongly suggest that one may optimize the antileukemic activity of anthracyclines by combining them with Apo-2 ligand treatment.
Previous studies have shown that doxorubicin, as many other DNA-damaging agents, activates p53-DNA binding.177 On the basis of the crucial role of p53 in the execution of some forms of apoptosis, it has been therefore speculated that p53 could play an important function in anthracycline cytotoxicity. In fact, the requirement for wild-type p53 for apoptosis after doxorubicin exposure has been demonstrated in rodent normal or minimally transformed fibroblasts and lymphocytes.178,179 However, the role of p53 mutations in drug-induced apoptosis and cytotoxicity in human tumor cells is much less clear (see Brown and Wouters for review180). As far as leukemic cells are concerned, it should be noted that most AML cell lines displayed mutated or deleted forms of p53, including U937 or HL-60 cells, which exhibit high sensitivity to DNR. This observation suggests that p53 plays a minor role in anthracycline-induced cytotoxicity in AML cells. However, some clinical studies have shown that p53 mutations predict poor clinical outcome in patients treated with anthracycline-containing regimens for hematologic neoplasias such as AML or large cell non-Hodgkin malignant lymphomas.181,182 It is therefore possible that loss of p53 function correlates with other drug resistance mechanisms or interferes with other apoptotic pathways. In this perspective, it is important to note that wild-type p53 is necessary for c-Myc-mediated facilitation of doxorubicin-induced apoptosis.183 Besides its role in apoptosis, p53 plays an important function in regulating cell cycle transition in doxorubicin-treated cells. Indeed, it has been shown that doxorubicin-induced p53 activation contributes to the induction of the WAF1/CIP1 p21 gene product, which is a strong inhibitor of cyclin-dependent kinases involved in G1 to S transition.184 Although p53-independent doxorubicin-induced WAF1/CIP1 has been described,185,186 this mechanism may account for G1 block after anthracycline exposure in p53 proficient cells. It has been suggested that WAF1 expression protects cells from doxorubicin-induced cytotoxicity because G1 block facilitates complete repair of DNA damage before the cells undergo DNA replication. In fact, it has been shown that high levels of constitutive WAF1/CIP1 protein are associated with chemoresistance in AML.187 Other cell cycle alterations have been described in doxorubicin-treated cells. Indeed, depending on the dose and cellular model, anthracyclines as many other genotoxic agents may also induce G2-M block because of p34cdc2 kinase inhibition. Indeed, previous studies have shown that doxorubicin prevented p34cdc2 dephosphorylation through a cdc25-independent mechanism, resulting in alteration of p34cdc2/cyclin B1-mediated complex.188 The mechanism by which anthracyclines interfere with p34cdc2 function has not been carefully examined. However, Kharbanda and coworkers189,190 have shown that most DNA damaging agents, including cytosine arabinoside, mitomycin C, and ionizing radiation, induce activation of p56/p53lyn, a tyrosine kinase of the Src family, which, in turn, phosphorylates and inactivates p34Cdc2. Whether or not Lyn is involved in anthracycline-induced p34cdc2 kinase inhibition and subsequent G2-M block should be confirmed.
It is now admitted that the extracellular matrix (ECM) plays an
important role in cell proliferation and survival through a complex
network of signals regulating cytoplasmic kinases, growth factor
receptors, and ion channels.191 In another study, it has been demonstrated that
It is evident from these investigations that apoptosis induced by
DNR brings into play a complex network of coordinated and highly
controlled events. Although the characterizations of these different
signaling pathways are still incomplete, we can at present attempt to
concisely recapitulate (with a little speculation) as to the individual
implication of these signaling pathways and mediators in DNR-induced
cell signaling (Figure 1).
Present knowledge suggests that in drug-sensitive cells clinically relevant concentrations of DNR trigger within minutes the generation of ROS that leads to a first wave of N-SMase activation, sphingomyelin hydrolysis, and consequently CER generation. This process makes the initial ROS burst the rate-limiting step in DNR-induced apoptosis signaling, and one can consider these early events (within the first 5 minutes) as the primary apoptotic initiation step. Then follows a cyclical cascade of ROS-dependent N-SMase activation and CER generation that perpetuates for about 4 hours until the apoptotic execution steps (caspase activation, mitochondrial depolarization, etc) come into play. It remains to be clearly determined, however, whether these cyclical events (which are p53-independent) are critical in the apoptotic signaling process. For example, does the inhibition of continual CER or ROS production significantly affect DNR-induced apoptosis (as is suggested by studies in which the overexpression of Bcl2 [thereby inhibiting DNR-induced apoptosis] failed to block initial CER generation)? The ROS-dependent sphingomyelin-CER pathway has been shown to be responsible for rapid activation of the MEKK1-SEK1-JNK cascade leading to enhanced DNA binding activity of the transcription factor AP-1. This latter pathway appears essential in DNR-triggered apoptosis. Of course, all of these events are absent in drug-resistant cells, and the literature proposes several potential mechanisms such as rapid CER metabolism into other lipid products (such as sphingosine-1-phosphate or glucosylceramide) that possess survival/proliferative properties. However, it remains to be determined to what extent (eg, which is dominant?) these metabolic events play a role in DNR resistance of myeloid leukemic cells. Remarkably, in drug-sensitive cells, DNR also triggers pathways that
should negatively regulate apoptosis. In parallel, a phospholipase
C-dependent DAG/raf-1/MEK cascade leading to activation of the
transcription factor NF- In conclusion, we now know that DNR triggers both positive and negative regulatory pathways of apoptosis; therefore, it is now essential to discriminate among resistance mechanisms of AML cells: those that lead to decreased drug-target interactions and those that interfere with cell death commitment. It will also most certainly be of great importance to delineate the role of effector-induced cell damage in programmed cell death signaling, and it will also be necessary to determine if the discrimination between apoptosis and necrosis is an essential phenomenon for in vivo therapeutics. Finally, this review incites for a reinterpretation of the actions of well-established therapeutic agents in the light of recent advances in the basic sciences that should allow cellular pharmacology of antineoplastic agents to continue gathering momentum in the perspective of overcoming drug resistance by defining pharmacologic strategies capable of sensitizing resistant tumor cells and/or protecting normal physiologic cells to DNR.197
We apologize to colleagues whose works were not cited because of the size restrictions of the review.
Submitted November 27, 2000; accepted April 5, 2001.
Supported by la Ligue Nationale Contre le Cancer and les Comités Départementaux du Gers, de l'Aveyron, du Lot et de la Haute-Garonne (J.P.J.), in part by l'Association pour la Recherche sur le Cancer grant 5526 (G.L.), by La Faculté de Médecine Toulouse-Rangueil (G.L.), and by le Centre National d'Etudes Spaciales (J.P.J.).
Reprints: Guy Laurent, INSERM E9910, Institut Claudius Régaud, 20 rue du Pont St Pierre, 31052 Toulouse, France; e-mail: laurent{at}icr.fnclcc.fr.
1. Myers CE, Chabner BA. Antracyclines. In: Chabner BA,Collins JM, eds. Cancer Chemotherapy. Principles and Practice. Philadelphia, PA: JB Lippincott; 1990:356-381. 2. Tritton TR. Cell surface actions of adriamycin. Pharmac Ther. 1991;49:293-309[CrossRef][Medline] [Order article via Infotrieve].
3.
Potmesil M, Kirschenbaum J, Israel M, Levin M, Khetarpal VK, Silber R.
Relationship of adriamycin concentrations to the DNA lesions induced in hypoxic and euoxic L1210 cells.
Cancer Res.
1983;43:3528-3533 4. Ross WE, Glaubiger K, Kohn KW. Qualitative and quantitative aspects of intercalator-induced DNA strand breaks. Biochim Biophys Acta. 1979;5629:41-50.
5.
Zwelling LA, Kerrigan D, Michaels S.
Cytotoxicity and DNA strand breaks by 5-iminodaunorubicin in mouse leukemia L1210 cells: comparison with adriamycin and 4'-(9-acridinylamino)- methanesulfon-m-aniside.
Cancer Res.
1982;42:2687-2691 6. Quillet-Mary A, Mansat V, Duchayne E, et al. Daunorubicin-induced internucleosomal DNA fragmentation in acute myeloid cell lines. Leukemia. 1996;10:417-425[Medline] [Order article via Infotrieve]. 7. Bailly JD, Muller C, Jaffrézou JP, et al. Lack of correlation between expression and function of P-glycoprotein in acute myeloid leukemic cells. Leukemia. 1995;9:799-807[Medline] [Order article via Infotrieve].
8.
Obeid LM, Linardic CM, Karolak LA, Hannun YA.
Programmed cell death induced by ceramide.
Science.
1993;259:1769-1771
9.
Haimovitz-Friedmann A, Kan CC, Ehleiter D, et al.
Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis.
J Exp Med.
1994;180:525-535 10. Jaffrézou JP, Levade T, Bettaieb A, et al. Daunorubicin induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J. 1996;15:2417-2424[Medline] [Order article via Infotrieve].
11.
Bezombes C, Ségui B, Cuvillier O, et al.
Lysosomal sphingomyelinase is not solicited for apoptosis signaling.
FASEB J.
2001;15:297-299 12. Bose R, Verheij M, Haimovitz-Friedman A, Scotto K, Fuks Z, Kolesnick R. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell. 1995;82:405-414[CrossRef][Medline] [Order article via Infotrieve].
13.
Xu J, Chen-Hsiung Y, Chen S, et al.
Involvement of de novo ceramide biosynthesis in tumor necrosis factor-
14.
Bourteele S, Hauber A, Döppler H, et al.
Tumor necrosis factor induces ceramide oscillations and negatively controls sphingolipid synthases by caspases in apoptotic Kym-1 cells.
J Biol Chem.
1998;273:31245-31251
15.
Jaffrézou JP, Maestre N, Mansat V, Bezombes C, Levade T, Laurent G.
Positive feedback control sphingomyelinase activity by ceramide.
FASEB J.
1998;12:999-1006 16. Verheij M, Bose R, Lin XH, et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature. 1996;380:75-79[CrossRef][Medline] [Order article via Infotrieve].
17.
Sawai H, Okazaki T, Yamamoto H, et al.
Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells.
J Biol Chem.
1995;270:27326-27331
18.
Lange-Carter CA, Johnson GL.
Ras-dependent growth factor regulation of MEK kinase in PC12 cells.
Science.
1994;265:1458-1461
19.
Johnson NL, Gardner AM, Diener KM, et al.
Signal transduction pathways regulated by mitogen-activated/extracellular response kinase kinase kinase induce cell death.
J Biol Chem.
1996;271:3229-3237
20.
Ichijo H, Nishida E, Irie K, et al.
Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signalling pathways.
Science.
1997;275:90-94
21.
Osborn MT, Chambers TC.
Role of the stress-activated/c-Jun NH2-terminal protein kinase pathway in the cellular response to adriamycin and other chemotherapeutic drugs.
J Biol Chem.
1996;271:30950-30955 22. Yu R, Shtil AA, Tan TH, Roninson IB, Kong AN. Adriamycin activates c-jun N-terminal kinase in human leukemia cells: a relevance to apoptosis. Cancer Lett. 1996;107:73-81[CrossRef][Medline] [Order article via Infotrieve].
23.
Mansat-De Mas V, Bezombes C, Quillet-Mary A, et al.
Implication of radical oxygen species in ceramide generation, c-Jun N-terminal kinase activation and apoptosis induced by daunorubicin.
Mol Pharmacol.
1999;56:867-874 24. Devary Y, Gottlieb RA, Smeal T, Karin M. The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases. Cell. 1992;71:1081-1091[CrossRef][Medline] [Order article via Infotrieve]. 25. Kharbanda S, Ren R, Pandley P, et al. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature. 1995;376:785-788[CrossRef][Medline] [Order article via Infotrieve].
26.
Shafman TD, Saleem A, Kyriakis J, Weichselbaum R, Kharbanda S, Kufe DW.
Defective induction of stress-activated protein kinase activity in ataxia-telangiectasia cells exposed to ionizing radiation.
Cancer Res.
1995;55:3242-3245
27.
Chen Y-R, Meyer CF, Tan T-H.
Persistant activation of c-Jun N-terminal kinase 1 (JNK1) in
28.
Kharbanda S, Pandey P, Ren R, Mayer BJ, Zon L, Kufe D.
c-Abl activation regulates induction of the SEK1/stress-activated protein kinase pathway in the cellular response to 1-
29.
Amato SF, Swart JM, Berg M, Wanebo HJ, Mehta SR, Chiles TC.
Transient stimulation of the c-Jun-NH2-terminal kinase/activator protein 1 pathway and inhibition of extracellular signal-regulated kinase are early effects in paclitaxel-mediated apoptosis in human B lymphoblasts.
Cancer Res.
1998;58:241-247
30.
Lee L-F, Li G, Templeton DJ, Ting JP.
Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-Jun NH2-terminal kinase (JNK/SAPK).
J Biol Chem.
1998;273:28253-28260
31.
Kyriakis JM, Avruch J.
Sounding the alarm: protein kinase cascades activated by stress and inflammation.
J Biol Chem.
1996;271:24313-24316
32.
Mansat V, Laurent G, Levade T, Bettaïeb A, Jaffrézou JP.
The protein kinase C activators phorbol esters and phosphatidylserine inhibit neutral sphingomyelinase activation, ceramide generation, and apoptosis triggered by daunorubicin.
Cancer Res.
1997;57:5300-5304
33.
Chmura SJ, Nodzenski E, Weichselbaum RR, Quintans J.
Protein kinase C inhibition induces apoptosis and ceramide production through activation of a neutral sphingomyelinase.
Cancer Res.
1996;56:2711-2714
34.
Linardic CM, Hannun YA.
Identification of a distinct pool of sphingomyelin involved in the sphingomyelin cycle.
J Biol Chem.
1994;269:23530-23537 35. Bailly JD, Skladanowski A, Bettaieb A, Mansat V, Larsen AK, Laurent G. Natural resistance of acute myeloid leukemia cell lines to mitoxantrone is associated with lack of apoptosis. Leukemia. 1997;11:1523-1532[CrossRef][Medline] [Order article via Infotrieve].
36.
Bettaieb A, Record M, Côme MG, et al.
Opposite effects of tumor necrosis factor
37.
Bezombes C, Maestre N, Laurent G, Levade T, Bettaieb A, Jaffrézou JP.
Restoration of TNF-
38.
Tepper AD, Ruurs P, Wiedmer T, Sims PJ, Borst J, van Blitterswijk WJ.
Sphingomyelin hydrolysis to ceramide during the execution phase of apoptosis results from phospholipid scrambling and alters cell-surface morphology.
J Cell Biol.
2000;150:155-164
39.
Luberto C, Hannun YA.
Sphingomyelin synthase, a potential regulator of intracellular levels of ceramide and diacylglycerol during SV40 transformation: does sphingomyelin synthase account for the putative phosphatidylcholine-specific phospholipase C?
J Biol Chem.
1998;273:14550-14559
40.
Hampton RY, Morand OH.
Sphingomyelin synthase and PKC activation.
Science.
1989;246:1050
41.
Ségui B, Bezombes C, Uro-Costes E, et al.
Stress-induced apoptosis is not mediated by endolysosomal ceramide.
FASEB J.
2000;14:36-47
42.
Coroneos E, Martinez M, McKenna S, Kester M.
Differential regulation of sphingomyelinase and ceramidase activities by growth factors and cytokines: implications for cellular proliferation and differentiation.
J Biol Chem.
1995;270:23305-23309 43. Cuvillier O, Pirianov G, Kleuser B, et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 1996;381:800-803[CrossRef][Medline] [Order article via Infotrieve].
44.
Cuvillier O, Rosenthal DS, Smulson ME, Spiegel S.
Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes.
J Biol Chem.
1998;273:2910-2916
45.
Kleuser B, Cuvillier O, Spiegel S.
1 46. Perez GI, Knudson CM, Leykin L, Korsmeyer SJ, Tilly JL. Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction. Nat Med. 1997;3:1228-1232[CrossRef][Medline] [Order article via Infotrieve].
47.
Shayman JA, Deshmukh GD, Mahdiyoun S, et al.
Modulation of renal epithelial cell growth by glucosylceramide: association with protein kinase C, sphingosine, and diacylglycerol.
J Biol Chem.
1991;266:22968-22974 48. Abe A, Radin NS, Shayman JA, et al. Structural and stereochemical studies of potent inhibitors of glucosylceramide synthase and tumor cell growth. J Lipid Res. 1995;36:611-621[Abstract].
49.
Rani CS, Abe A, Chang Y, et al.
Cell cycle arrest induced by an inhibitor of glucosylceramide synthase: correlation with cyclin-dependent kinases.
J Biol Chem.
1995;270:2859-2867
50.
Liu YY, Han TY, Giulano AE, Cabot MC.
Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells.
J Biol Chem.
1999;274:1140-1146
51.
Lavie Y, Cao H-T, Volner A, et al.
Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells.
J Biol Chem.
1997;272:1682-1687
52.
Liu Y-Y, Han T-Y, Giulano AE, Hansen N, Cabot MC.
Uncoupling ceramide glycosylation by transfection of glucosylceramide synthase antisense reverses adriamycin resistance.
J Biol Chem.
2000;275:7138-7143 53. Come MG, Bettaieb A, Skladanowski A, Larsen AK, Laurent G. Alteration of the daunorubicin-triggered sphingomyelin-ceramide pathway and apoptosis in MDR cells: influence of drug transport abnormalities. Int J Cancer. 1999;81:580-587[CrossRef][Medline] [Order article via Infotrieve].
54.
Lavie Y, Cao H-t, Bursten SL, Giulano AE, Cabot MC.
Accumulation of glucosylceramide in multidrug-resistant cancer cells.
J Biol Chem.
1996;271:19530-19536 55. Lucci A, Cho WI, Han TY, Giulano AE, Cabot MC. Glucosylceramide: a marker for multiple-drug resistant cancers. Anticancer Res. 1998;18:475-480[Medline] [Order article via Infotrieve]. 56. Lucci A, Han TY, Liu YY, Giuliano AE, Cabot MC. Modification of ceramide metabolism increases cancer cell sensitivity to cytotoxics. Int J Oncol. 1999;15:541-546[Medline] [Order article via Infotrieve]. 57. Lucci A, Han TY, Liu YY, Giuliano AE, Cabot MC. Multidrug resistance modulators and doxorubicin synergize to elevate ceramide levels and elicit apoptosis in drug-resistant cancer cells. Cancer. 1999;86:299-310[CrossRef].
58.
Cabot MC, Giulano AE, Han T-Y, Liu Y-Y.
SDZ PSC 833, the cyclosporin A analogue and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drug-resistant cancer cells.
Cancer Res.
1999;59:880-885 59. Veldman RJ, Sietsma H, Klappa K, Hoeckstr D, Kok JW. Inhibition of P-glycoprotein activity and chemosensitization of multidrug-resistant ovarian carcinoma 2780 AD cells by dexanoyl glucosylceramide. Biochem Res Commun. 1999;266:492-496. 60. Allouche M, Bettaïeb A, Vindis C, Rousse A, Grignon C, Laurent G. Influence of Bcl-2 overexpression on the ceramide pathway in daunorubicin-induced apoptosis of leukemic cells. Oncogene. 1997;14:1837-1845[CrossRef][Medline] [Order article via Infotrieve]. 61. Martin SJ, Takayama S, McGahon A, et al. Inhibition of ceramide-induced apoptosis by Bcl-2. Cell Death Differ. 1995;2:253-257.
62.
Jarvis WDJ, Fornari FA, Browning JL, Gewirtz DA, Kolesnick RN, Grant SG.
Attenuation of ceramide-induced apoptosis by diglyceride in human myeloid leukemia cells.
J Biol Chem.
1994;269:31685-31692
63.
Jarvis WD, Fornari FA, Traylor RS, et al.
Induction of apoptosis and potentiation of ceramide-mediated cytotoxicity by sphingoid bases in human myeloid leukemia cells.
J Biol Chem.
1996;271:8275-8284
64.
Miyajima A, Mui AL-F, Ogorochi T, Sakamaki K.
Receptors for granulo-macrophage colony-stimulating factor, interleukin-3, and interleukin-5.
Blood.
1993;82:1960-1974
65.
Lotem J, Sachs L.
Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor 66. Kaplinski C, Lotem J, Sachs L. Protection of human myeloid leukemic cells against doxorubicin-induced apoptosis by granulocyte-macrophage colony-stimulating factor and interleukin 3. Leukemia. 1996;10:460-465[Medline] [Order article via Infotrieve].
67.
Laredo J, Huyn A, Muller C, et al.
Effect of the protein kinase C inhibitor staurosporine on chemosensitivity to daunorubicin of normal and leukemic fresh myeloid cells.
Blood.
1994;84:229-237
68.
Plo I, Lautier D, Casteran N, Dubreuil P, Arock M, Laurent G.
Kit activation inhibits daunorubicin-induced sphingomyelin cycle and apoptosis through a phospholipase C 69. Sinha BK, Mimmaugh EG. Free radicals and anticancer drug resistance: oxygen free radicals in the mechanisms of drug cytotoxicity and resistance by certain tumors. Free Radicals Biol Med. 1990;8:567-581[CrossRef][Medline] [Order article via Infotrieve]. 70. Pedersen JZ, Marcocci L, Rossi L, Mavelli I, Rotilio G. Generation of daunomycin radicals on the outer side of the erythrocyte membrane. Biochem Pharmacol. 1990;168:240-247. 71. Gutteridge JM. Lipid peroxidation and possible hydroxyl radical formation stimulated by the self-reduction of a doxorubicin-iron (III) complex. Biochem Pharmacol. 1984;33:1725-1728[CrossRef][Medline] [Order article via Infotrieve].
72.
Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM, Hannun YA.
Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-
73.
Singh I, Pahan K, Khan M, Singh A.
Cytokine-mediated induction of ceramide production is redox-sensitive.
J Biol Chem.
1998;273:20354-20362
74.
Garcia-Ruiz C, Colell A, Mari M, Morales A, Fernandez-Checa JC.
Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive species.
J Biol Chem.
1997;272:11369-11377
75.
Quillet-Mary A, Jaffrézou JP, Mansat V, Bordier C, Naval J, Laurent G.
Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis.
J Biol Chem.
1997;272:21388-21395 76. Verhaegen S, McGowan AJ, Brophy AR, Fernandes RS, Cotter TG. Inhibition of apoptosis by antioxidants in the human HL-60 leukaemia cell line. Biochem Pharmacol. 1995;50:1021-1029[CrossRef][Medline] [Order article via Infotrieve]. 77. Fiorani M, Cantoni O, Tasinato A, Boscoboinik D, Azzi A. Hydrogen peroxide- and fetal bovine serum-induced DNA synthesis in vascular smooth muscle cells: positive and negative regulation by protein kinase C isoforms. Biochim Biophys Acta. 1995;1269:98-104[Medline] [Order article via Infotrieve].
78.
Ohmori S, Shirai Y, Sakai N, et al.
Three distinct mechanisms for translocation and activation of the delta subspecies of protein kinase C.
Mol Cell Biol.
1998;18:5263-5271 79. Chen CC, Liau CS, Lee YT. Tumor necrosis factor-alpha, platelet-activating factor, and hydrogen peroxide activate protein kinase C subtypes alpha and epsilon in human saphenous vein endothelial cells. J Cardiovasc Pharmacol. 1996;28:240-244[CrossRef][Medline] [Order article via Infotrieve].
80.
Devary Y, Rosette C, DiDonato JA, Karin M.
NF- 81. Kasid U, Suy S, Dent P, Ray S, Whiteside TL, Sturgill TW. Activation of Raf by ionizing radiation. Nature. 1996;382:813-816[CrossRef][Medline] [Order article via Infotrieve]. 82. Suy S, Anderson WB, Dent P, Chang E, Kasid U. Association of Grb2 with Sos and Ras with Raf-1 upon gamma irradiation of breast cancer cells. Oncogene. 1997;15:53-61[CrossRef][Medline] [Order article via Infotrieve].
83.
Konishi H, Tanaka M, Takemura Y, et al.
Activation of protein kinase C by tyrosine phosphorylation in response to H2O2.
Proc Natl Acad Sci U S A.
1997;94:11233-11237 84. Aikawa AR, Komuro I, Yamazaki T, et al. Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. J Clin Invest. 1997;100:1813-1821[Medline] [Order article via Infotrieve].
85.
Min DS, Kim E-G, Exton JH.
Involvement of tyrosine phosphorylation and protein kinase C in the activation of phospholipase D by H2O2 in swiss 3T3 fibroblasts.
J Biol Chem.
1998;273:29986-29994
86.
Russo T, Zambrano N, Esposito F, et al.
A p53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress.
J Biol Chem.
1995;270:29386-29391
87.
Guyton KZ, Liu Y, Gorospe M, Xu Q, Holbrook NJ.
Activation of mitogen-activated protein kinase by H2O2: role in cell survival following oxidant injury.
J Biol Chem.
1996;271:4138-4142
88.
Baeuerle PA, Henkel T.
Function and activation of NF-
89.
Wang C-Y, Mayo MW, Baldwin AS.
TNF-
90.
Posada J, Vichi P, Tritton TR.
Protein kinase C in adriamycin action and resistance in mouse sarcoma 180 cells.
Cancer Res.
1989;49:6634-6639
91.
Bettaieb A, Plo I, Mansat-De Mas V, et al.
Daunorubicin- and mitoxantrone-triggered phosphatidylcholine hydrolysis: implication in drug-induced ceramide generation.
Mol Pharmacol.
1999;55:118-125
92.
Kolesnick R, Fuks Z.
Ceramide: a signal for apoptosis or mitogenesis?
J Exp Med.
1995;181:1949-1952
93.
Bjorkoy G, Overvathn A, Diaz-Meco MT, Moscat J, Johansen T.
Evidence for a bifurcation of the mitogenic signaling pathway activated by Ras and phosphatidylcholine-hydrolyzing phospholipase C.
J Biol Chem.
1995;270:21299-21306
94.
Van Dijk MCM, Hilkmann H, van Blitterswijk WJ.
Platelet-derived growth factor activation of mitogen-activated protein kinase depends on the sequential activation of phosphatidylcholine-specific phospholipase C, protein kinase C-
95.
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME.
Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.
Science.
1995;270:1326-1331 96. Gokhale PC, Soldatenkov V, Wang FH, Rahman A, Dritschilo A, Kasid U. Antisense raf oligodeoxyribonucleotide is protected by liposomal encapsulation and inhibits Raf-1 protein expression in vitro and in vivo: implication for gene therapy of radioresistant cancer. Gene Ther. 1997;4:1289-1299[CrossRef][Medline] [Order article via Infotrieve]. 97. Pirollo KF, Hao Z, Rait A, Ho CW, Chang EH. Evidence supporting a signal transduction pathway leading to the radiation-resistant phenotype in human tumor cells. Biochem Biophys Res Commun. 1997;230:196-201[CrossRef][Medline] [Order article via Infotrieve].
98.
Berra E, Diaz-Meco MT, Dominguez I, et al.
Protein kinase C 99. Berra E, Municio MM, Sanz L, Frutos S, Diaz-Meco MT, Moscat J. Positioning atypical PKC isoforms in the UV-induced apoptotic signaling cascade. Mol Cell Biol. 1997;17:4346-4354[Abstract].
100.
Murray NR, Fields AP.
Atypical protein kinase C 101. Diaz-Laviada I, Larrodera P, Diaz-Meco MT, et al. Evidence for a role of phosphatidylcholine-hydrolysing phospholipase C in the regulation of protein kinase C by ras and src oncogenes. EMBO J. 1990;9:3907-3912[Medline] [Order article via Infotrieve]. 102. Rao P, Kitamura T, Miyajima A, Mufson RA. Human IL-3 receptor signaling: rapid induction of phosphatidylcholine hydrolysis is independent of protein kinase C but dependent on tyrosine phosphorylation in transfected NIH 3T3 cells. J Immunol. 1995;154:1664-1674[Abstract].
103.
Rao P, Mufson RA.
Human interleukin-3 stimulates a phosphatidylcholine specific phospholipase C and protein kinase C translocation.
Cancer Res.
1994;54:777-781
104.
Machleidt T, Krämer B, Adam D, et al.
Function of the p55 tumor necrosis factor receptor "death domain" mediated by phosphatidylcholine-specific phospholipase C.
J Exp Med.
1996;184:725-733
105.
Franke TF, Kaplan DR, Cantley LC, Toker A.
Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-biphophate.
Science.
1997;275:665-668 106. Franke TF, Kaplan DR, Cantley LC. PI3K: downstream AKTion blocks apoptosis. Cell. 1997;88:435-437[CrossRef][Medline] [Order article via Infotrieve].
107.
Toker A, Meyer M, Reddy KK, et al.
Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3.
J Biol Chem.
1994;269:32358-32367
108.
Nakanishi H, Brewer KA, Exton JH.
Activation of the
109.
Bae YS, Cantley LG, Chen C-S, Kim S-R, Kwon K-S, Rhee SG.
Activation of phospholipase C-
110.
Price BD, Youmell MB.
The phosphatidylinositol 3-kinase inhibitor wortmannin sensitizes murine fibroblasts and human tumor cells to radiation and blocks induction of p53 following DNA damage.
Cancer Res.
1996;56:246-250 111. Kulik G, Klippel A, Weber MJ. Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol. 1997;17:1595-1606[Abstract]. 112. Plo I, Bettaieb A, Payrastre B, et al. Phosphoinositide 3-kinase/Akt-mediated survival pathway is activated by daunorubicin in human acute myeloid leukemia cell lines. FEBS Lett. 1999;452:150-154[CrossRef][Medline] [Order article via Infotrieve]. 113. O'Gorman DM, Mc Kenna SL, McGahon AJ, Knox KA, Cotter TG. Sensitization of HL60 human apoptosis by inhibition of PI3-kinase survival signals. Leukemia. 2000;14:602-611[CrossRef][Medline] [Order article via Infotrieve]. 114. Rodriguez-Viciana P, Warne PH, Khwaja A, et al. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell. 1997;89:457-467[CrossRef][Medline] [Order article via Infotrieve].
115.
Varticovski L, Daley GQ, Jackson P, Baltimore D, Cantley LC.
Activation of phosphatidylinositol 3-kinase in cells expressing abl oncogene variants.
Mol Cell Biol.
1991;11:1107-1113 116. Skorski T, Bellacosa A, Nieborovska-Skorska M, et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J. 1997;16:6151-6161[CrossRef][Medline] [Order article via Infotrieve].
117.
Skorski T, Kanakaraj P, Nieborovska-Skorska M, et al.
Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells.
Blood.
1995;86:726-736 118. Casteran N, Rottapel R, Beslu N, Lecocq E, Birnbaum D, Dubreuil P. Analysis of the mitogenic pathway of the FLT3 receptor and characterization in its C terminal region of a specific binding site for the PI3-kinase. Cell Mol Biol. 1994;40:443-456[Medline] [Order article via Infotrieve].
119.
Del Peso L, Gonzales-Garcia M, Page C, Herrera R, Nunez G.
Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt.
Science.
1997;278:687-689
120.
Kennedy SG, Wagner AJ, Conzen SD, et al.
The PI 3-kinase/Akt signaling pathway delivers an apoptotic signal.
Genes Dev.
1997;11:701-713
121.
Cardone MH, Roy N, Stennicke HR, et al.
Regulation of cell death protease caspase-9 by phosphorylation.
Science.
1998;282:1318-1321
122.
Zhou H, Summers SA, Birbaum MJ, Pittman RN.
Inhibition of Akt kinase by cell-permeable ceramide and its implication for ceramide-induced apoptosis.
J Biol Chem.
1998;273:16568-16575
123.
Piret B, Pirette J.
Topoisimerase poisons activate the transcription factor NF-kappaB in ACH-2 and CEM cells.
Nucleic Acids Res.
1996;24:4242-4248
124.
Boland MP, Foster SJ, O'Neill LAJ.
Daunorubicin activates NF
125.
Das KC, White CW.
Activation of NF-
126.
Hellin A-C, Calmant P, Gielin J, Bours V, Merville M-P.
Nuclear factor-
127.
Bentires-Alj M, Hellin A-C, Ameyar M, Chouaib S, Merville M-P, Bours V.
Stable inhibition of nuclear factor kB in cancer cells does not increase sensitivity to cytotoxic drugs.
Cancer Res.
1999;59:811-815
128.
Brach MA, Kharbanda SM, Herrmann F, Kufe DW.
Activation of the transcription factor kB in human KG-1 myeloid leukemia cells treated with 1- 129. Slater AF, Kimland M, Jiang SA, Orrenius S. Constitutive nuclear NF kappa B/rel DNA-binding activity of rat thymocytes is increased by stimuli that promote apoptosis, but not inhibited by pyrrolidine dithiocarbamate. Biochem J. 1995;312:833-838.
130.
Schutze SK, Potthoff T, Machleidt D, Berkovic K, Wiegmann K, Kronke M.
TNF activates NF- 131. Mansat V, Bettaieb A, Levade T, Laurent G, Jaffrézou JP. Serine-protease inhibitors block neutral sphingomyelinase activation, ceramide generation and apoptosis triggered by daunorubicin. FASEB J. 1997;11:695-702[Abstract].
132.
Johns LD, Sarr T, Ranges GE.
Inhibition of ceramide pathway does not affect ability of TNF-
133.
Betts JC, Agranoff AB, Nabel GJ, Shayman JA.
Dissociation of endogenous cellular ceramide from NF-
134.
Lallena MJ, Diaz-Meco MT, Bren G, Paya CV, Moscat J.
Activation of IkappaB kinase beta by protein kinase C isoforms.
Mol Cell Biol.
1999;19:2180-2188
135.
Nidai Ozes O, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB.
NF-
136.
Romashkova JA, Makarov SS.
NF-
137.
Wu M, Lee H, Bellas RE, et al.
Inhibition of NF-
138.
Bargou RC, Emmerich F, Krappmann D, et al.
Constitutive nuclear factor-
139.
Pyatt DW, Stillman WS, Yang Y, Gross S, Zheng J-h, Irons RD.
An essential role for NF-
140.
Beg AA, Baltimore D.
An essential role for NF-
141.
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM.
Suppression of TNF- 142. Brockman JA, Scherer DC, McKinsey TA, et al. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol. 1995;15:2809-2818[Abstract]. 143. Palombello V, Rando O, Goldberg A, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994;78:773-785[CrossRef][Medline] [Order article via Infotrieve].
144.
Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M.
Immunosuppression by glucocorticoids: inhibition of NF-
145.
Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS.
Role of transcriptional activation of IkBa in mediation of immunosuppression by glucocorticoids.
Science.
1995;270:283-286 146. Wang CY, Cusack JC Jr, Liu R, Baldwin AS Jr. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med. 1999;5:412-417[CrossRef][Medline] [Order article via Infotrieve].
147.
Diaz-Meco MT, Lallena M-J, Monjas A, Frutos S, Moscat J.
Inactivation of the inhibitory 148. Friesen C, Herr I, Krammer PH, Debatin KM. Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med. 1996;2:574-577[CrossRef][Medline] [Order article via Infotrieve]. 149. Müller M, Strand S, Hug H, et al. Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J Clin Invest. 1997;99:403-413[Medline] [Order article via Infotrieve].
150.
Fulda S, Sieverts H, Friesen C, Herr I, Debatin KM.
The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells.
Cancer Res.
1997;57:3823-3829 151. Herr I, Wilhelm D, Bohler T, Angel P, Debatin KM. Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J. 1997;16:6200-6208[CrossRef][Medline] [Order article via Infotrieve].
152.
Eischen CM, Kottke TJ, Martins LM, et al.
Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions.
Blood.
1997;90:935-943
153.
Villunger A, Egle A, Kos M, et al.
Drug-induced apoptosis is associated with enhanced Fas (APO-1/CD95) ligand expression but occurs independently of Fas (APO-1/CD95) signaling in human T-acute lymphatic leukemia cells.
Cancer Res.
1997;57:3331-3334
154.
Wesselborg S, Engels IH, Rossmann E, Los M, Schulze-Osthoff K.
Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction.
Blood.
1999;93:3053-3063
155.
Micheau O, Solary E, Hammann A, Dimanche-Boitrel M-T.
Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs.
J Biol Chem.
1999;274:7987-7992
156.
Rehemtulla A, Hamilton CA, Chinnaiyan AM, Dixit VM.
Ultraviolet radiation-induced apoptosis is mediated by activation of CD-95 (Fas/APO-1).
J Biol Chem.
1997;272:25783-25786
157.
Aragane Y, Kulms D, Metze D, et al.
Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L.
J Cell Biol.
1998;140:171-182 158. Belka C, Marini P, Lepple-Wienhues A, et al. The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation. Oncogene. 1999;18:4983-4992[CrossRef][Medline] [Order article via Infotrieve]. 159. Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95(Fas/Apo-1) death-inducing signaling complex. Cell. 1996;85:817-827[CrossRef][Medline] [Order article via Infotrieve].
160.
Kataoka T, Schroter M, Hahne M, et al.
FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation.
J Immunol.
1998;161:3936-3942
161.
Los M, Herr I, Friesen C, Fulda S, Schulze-Osthoff K, Debatin KM.
Cross-resistance of CD95- and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases).
Blood.
1997;90:3118-3129
162.
Dbaibo GS, Perry DK, Gamard CJ, et al.
Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)- 163. Tepper AD, de Vries E, van Blitterswijk WJ, Borst J. Ordering of ceramide formation, caspase activation, and mitochondrial changes during CD95- and DNA damage-induced apoptosis. J Clin Invest. 1999;103:971-978[Medline] [Order article via Infotrieve].
164.
Zeytun A, Hassuneh M, Nagarkatti M, Nagarkatti PS.
Fas-Fas ligand-based interactions between tumor cells and tumor-specific cytotoxic T lymphocytes: a lethal two-way street.
Blood.
1997;90:1952-1959
165.
Strand S, Hofmann WJ, Hug H, et al.
Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells 166. Schmidt-Wolf IG, Lefterova P, Johnston V, et al. Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells. Cell Immunol. 1996;169:85-90[CrossRef][Medline] [Order article via Infotrieve]. 167. Frost P, Ng CP, Belldegrun A, Bonavida B. Immunosensitisation of prostate carcinoma cell lines for lymphocytes (CTL, TIL, LAK)-mediated apoptosis via the Fas-Fas-ligand pathway of cytotoxicity. Cell Immunol. 1997;180:70-83[CrossRef][Medline] [Order article via Infotrieve].
168.
Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel M-T.
Sensitization of cancer cells treated with cytotoxic drugs to Fas-mediated cytotoxicity.
J Natl Cancer Inst.
1997;89:783-789 169. Classen CF, Fulda S, Friesen C, Debatin KM. Decreased sensitivity of drug-resistant cells towards T cell cytotoxicity. Leukemia. 1999;13:410-418[CrossRef][Medline] [Order article via Infotrieve]. 170. Cai Z, Stancou R, Körner M, Chouaib S. Impairment of Fas-antigen expression in adriamycin-resistant but not TNF-resistant MCF-7 tumor cells. Int J Cancer. 1996;68:535-546[CrossRef][Medline] [Order article via Infotrieve].
171.
Landowski TH, Gleason-Guzman MC, Dalton W.
Selection for drug resistance results in resistance to Fas-mediated apoptosis.
Blood.
1997;89:1854-1861
172.
Barcena A, Park SW, Banapour B, Muench MO, Mechetner E.
Expression of Fas/CD95 and Bcl-2 by primitive hematopoietic progenitors freshly isolated from human fetal liver.
Blood.
1996;88:2013-2025 173. Dirks W, Schöne S, Uphoff C, Quentmeier H, Pradella S, Drexler HG. Expression and function of CD95 (FAS/apo-1) in leukemia-lymphoma tumour lines. Br J Haematol. 1997;96:584-593[CrossRef][Medline] [Order article via Infotrieve].
174.
Iijima N, Miyamura K, Itou T, Tanimoto M, Sobue R, Saito H.
Functional expression of Fas (CD95) in acute myeloid leukemia cells in the context of CD34 and CD38 expression: possible correlation with sensitivity to chemotherapy.
Blood.
1997;90:4901-4909
175.
Wen J, Ramadevi N, Nguyen D, Perkins C, Worthington E, Bhalla K.
Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells.
Blood.
2000;96:3900-3906
176.
Sheikh MS, Burns TF, Huang Y, et al.
p53-dependent and -independent regulation of the death receptor killer/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha.
Cancer Res.
1998;58:1593-1598
177.
Tishler RB, Calderwood SK, Coleman N, Price BD.
Increase in sequence specific DNA binding by p53 following treatment with chemotherapeutic and DNA damaging agents.
Cancer Res.
1993;53:2212-2216
178.
Lowe SW, Bodis S, McClatchey A, et al.
p53 status and the efficacy of cancer therapy in vivo.
Science.
1994;266:807-810 179. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993;74:957-967[CrossRef][Medline] [Order article via Infotrieve].
180.
Brown JM, Wouters BG.
Apoptosis, p53, and tumor cell sensitivity to anticancer agents.
Cancer Res.
1999;59:1391-1399
181.
Wattel E, Preudhomme C, Hecquet B, et al.
p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies.
Blood.
1994;84:3148-3157 182. Navaratnam S, Williams GJ, Rubinger M, et al. Expression of p53 predicts treatment failure in aggressive non-Hodgkin's lymphomas. Leuk Lymphoma. 1998;29:139-144[Medline] [Order article via Infotrieve].
183.
Han J-W, Dionne CA, Kedersha NL, Goldmacher VS.
p53 status affects the rate of the onset but not the overall extent of doxorubicin-induced cell death in Rat-1 fibroblasts constitutively expressing c-Myc.
Cancer Res.
1997;57:176-182 184. El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817-825[CrossRef][Medline] [Order article via Infotrieve]. 185. Vikhanskaya F, D'Incalci M, Broggini M. Decreased cytotoxic effects of doxorubicin in a human ovarian cancer-cell line expressing wild-type p53 and WAF1/CIP1 genes. Int J Cancer. 1995;61:397-401[Medline] [Order article via Infotrieve].
186.
Gartenhaus RB, Wang P, Hoffmann P.
Induction of the WAF1/CIP1 protein and apoptosis in human T-cell leukemia virus type I-transformed lymphocytes after treatment with adriamycin by using a p53-independent pathway.
Proc Natl Acad Sci U S A.
1996;93:265-268 187. Zhang W, Kornblau SM, Kobayashi T, Gambel A, Claxton D, Deisseroth AB. High levels of constitutive WAF1/Cip1 protein are associated with chemoresistance in acute myelogenous leukemia. Clin Cancer Res. 1995;1:1051-1057[Abstract]. 188. Ling Y-H, El-Naggar AK, Priebe W, Perez-Soler R. Cell cycle-dependent cytotoxicity, G2/M phase arrest, and disruption of p34cdc2/cyclin B1 activity induced by doxorubicin in synchronized P388 cells. Mol Pharmacol. 1996;49:832-841[Abstract].
189.
Kharbanda S, Yuan ZM, Rubin E, Weichselbaum R, Kufe D.
Activation of Src-like p56/p53lyn tyrosine kinase by ionizing radiation.
J Biol Chem.
1994;269:20739-20743 190. Kharbanda S, Yuan ZM, Taneja N, Weichselbaum R, Kufe D. p56/p53lyn tyrosine kinase activation in mammalian cells treated with mitomycin C. Oncogene. 1994;9:3005-3011[Medline] [Order article via Infotrieve].
191.
Giancotti FG, Ruoslahti E.
Integrin signaling.
Science.
1999;285:1028-1032 192. Sethi T, Rintoul RC, Moore SM, et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med. 1999;5:662-668[CrossRef][Medline] [Order article via Infotrieve].
193.
Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS.
Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines.
Blood.
1999;93:1658-1667
194.
Verfaillie CM.
Adhesion receptors as regulators of the hematopoietic process.
Blood.
1998;92:2609-2612 195. Chen JJW, Wu R, Yang PC, et al. Profiling expression patterns and isolating differentially expressed genes by cDNA microarray system with colorimetry detection. Genomics. 1998;51:313-324[CrossRef][Medline] [Order article via Infotrieve].
196.
Kudoh K, Ramana M, Ravata R, et al.
Monitoring the expression profiles of doxorubicin-induced and doxorubicin-resistant cancer cells by cDNA microarray.
Cancer Res.
2000;60:4161-4166
197.
Hannun YA.
Apoptosis and the dilemma of cancer chemotherapy.
Blood.
1997;89:1845-1853
© 2001 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  G. Gausdal, B. T. Gjertsen, E. McCormack, P. Van Damme, R. Hovland, C. Krakstad, O. Bruserud, K. Gevaert, J. Vandekerckhove, and S. O. Doskeland Abolition of stress-induced protein synthesis sensitizes leukemia cells to anthracycline-induced death Blood, March 1, 2008; 111(5): 2866 - 2877. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Duan, W. K. Bleibel, R. S. Huang, S. J. Shukla, X. Wu, J. A. Badner, and M. E. Dolan Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity Cancer Res., June 1, 2007; 67(11): 5425 - 5433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Pham, C. Bubici, F. Zazzeroni, J. R. Knabb, S. Papa, C. Kuntzen, and G. Franzoso Upregulation of Twist-1 by NF-{kappa}B Blocks Cytotoxicity Induced by Chemotherapeutic Drugs Mol. Cell. Biol., June 1, 2007; 27(11): 3920 - 3935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, D. White, L. He, R. L. Miller, and D. E. Spaner Toll-like Receptor-7 Tolerizes Malignant B Cells and Enhances Killing by Cytotoxic Agents Cancer Res., February 15, 2007; 67(4): 1823 - 1831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mattia, V. Gottifredi, K. McKinney, and C. Prives p53-Dependent p21 mRNA Elongation Is Impaired when DNA Replication Is Stalled Mol. Cell. Biol., February 15, 2007; 27(4): 1309 - 1320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Beyne-Rauzy, N. Prade-Houdellier, C. Demur, C. Recher, J. Ayel, G. Laurent, and V. Mansat-De Mas Tumor necrosis factor-{alpha} inhibits hTERT gene expression in human myeloid normal and leukemic cells Blood, November 1, 2005; 106(9): 3200 - 3205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Avellino, S. Romano, R. Parasole, R. Bisogni, A. Lamberti, V. Poggi, S. Venuta, and M. F. Romano Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells Blood, August 15, 2005; 106(4): 1400 - 1406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Catley, Y.-T. Tai, R. Shringarpure, R. Burger, M. T. Son, K. Podar, P. Tassone, D. Chauhan, T. Hideshima, L. Denis, et al. Proteasomal Degradation of Topoisomerase I Is Preceded by c-Jun NH2-Terminal Kinase Activation, Fas Up-Regulation, and Poly(ADP-Ribose) Polymerase Cleavage in SN38-Mediated Cytotoxicity against Multiple Myeloma Cancer Res., December 1, 2004; 64(23): 8746 - 8753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tourneur, S. Delluc, V. Levy, F. Valensi, I. Radford-Weiss, O. Legrand, J. Vargaftig, C. Boix, E. A. Macintyre, B. Varet, et al. Absence or Low Expression of Fas-Associated Protein with Death Domain in Acute Myeloid Leukemia Cells Predicts Resistance to Chemotherapy and Poor Outcome Cancer Res., November 1, 2004; 64(21): 8101 - 8108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman Doxorubicin Induces Apoptosis in Normal and Tumor Cells via Distinctly Different Mechanisms: INTERMEDIACY OF H2O2- AND p53-DEPENDENT PATHWAYS J. Biol. Chem., June 11, 2004; 279(24): 25535 - 25543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Grazide, A.-D. Terrisse, S. Lerouge, G. Laurent, and J.-P. Jaffrezou Cytoprotective Effect of Glucosylceramide Synthase Inhibition against Daunorubicin-induced Apoptosis in Human Leukemic Cell Lines J. Biol. Chem., April 30, 2004; 279(18): 18256 - 18261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. FOGLI, P. NIERI, and M. C. BRESCHI The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage FASEB J, April 1, 2004; 18(6): 664 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hueber, M. Weller, G. Welsandt, N. Kociok, B. Kirchhof, and P. Esser Characterization of Daunorubicin-Induced Apoptosis in Retinal Pigment Epithelial Cells: Modulation by CD95L Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 2851 - 2857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Hur, J. Lewis, Q. Yang, Y. Lin, H. Nakano, S. Nedospasov, and Z.-g. Liu The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation Genes & Dev., April 1, 2003; 17(7): 873 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M.-D. Mas, H. Hernandez, I. Plo, C. Bezombes, N. Maestre, A. Quillet-Mary, R. Filomenko, C. Demur, J.-P. Jaffrezou, and G. Laurent Protein kinase Czeta mediated Raf-1/extracellular-regulated kinase activation by daunorubicin Blood, February 15, 2003; 101(4): 1543 - 1550. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Guzman, C. F. Swiderski, D. S. Howard, B. A. Grimes, R. M. Rossi, S. J. Szilvassy, and C. T. Jordan Preferential induction of apoptosis for primary human leukemic stem cells PNAS, December 10, 2002; 99(25): 16220 - 16225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bezombes, A. de Thonel, A. Apostolou, T. Louat, J.-P. Jaffrezou, G. Laurent, and A. Quillet-Mary Overexpression of Protein Kinase Czeta Confers Protection Against Antileukemic Drugs by Inhibiting the Redox-Dependent Sphingomyelinase Activation Mol. Pharmacol., December 1, 2002; 62(6): 1446 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Abstracts of Presentations at the Meeting of the Association of Clinical Scientists in Salt Lake City, UT, on 8 to 11 May 2002 Ann. Clin. Lab. Sci., July 1, 2002; 32(3): 312 - 333. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
B activation...
B,
as well as the Fas/Fas-ligand system. These pathways are themselves
influenced by a number of lipid products (diacylglycerol, sphingosine-1
phosphate, and glucosyl ceramide), reactive oxygen species, oncogenes
(such as the tumor suppressor gene p53), protein kinases
(protein kinase C and phosphoinositide-3 kinase), and external stimuli
(hematopoietic growth factors and the extracellular matrix). In light
of the complexity and diversity of these observations, a comprehensive
review has been attempted toward the understanding of their individual
implication (and regulation) in daunorubicin-induced signaling.
(Blood. 2001;98:913-924)
-radiation in bovine endothelial cells.
OH). By employing electron spin resonance together with
a spin-trap such as DMPO (5,5-dimethyl-1-pyrroline N-oxide),
anthracycline-induced 
or 
"atypical" isoforms that have been involved in cell proliferation
and/or survival.
, 
, and 
isoforms,
B activation in DNR-induced
apoptosis
) which
phosphorylate residues 32 and 36 of I
a mechanism of immune evasion?
Nat Med.
1996;2:1361-1366