Abstinence from cocaine reduces high-risk responses on a gambling task.
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Adult↗
Biomedical subjects
S Grant
Publications and source records attributed to S Grant.
The effect of amlodipine on respiratory and pulmonary vascular responses to hypoxia in mountaineers.
Calcium antagonists are known to reduce the incidence of high-altitude pulmonary oedema, but the mechanism is unclear. The aim of this study was to examine the effects of the calcium antagonist, amlodipine, on cardiac and respiratory responses in normoxia and hypoxia. Fourteen normal subjects aged 31+/-4 yrs who had climbed to altitudes of 5,000-7,500 m without problems were randomly assigned to a double-blind crossover trial of amlodipine versus placebo, using sea-level inspiratory hypoxia to simulate altitude. Doppler echocardiographic estimates of resting pulmonary haemodynamics and cycle ergometer test results of cardiorespiratory responses to exercise were recorded in normoxia and hypoxia. It was found that, although hypoxic pulmonary vasoconstriction (HPV) was not significantly reduced by amlodipine, the effect of the drug on HPV was inversely related to the serum level of amlodipine. Amlodipine did not alter left ventricular function measured echocardiographically. During exercise, amlodipine increased breathlessness, measured using standard scales, in both normoxia and hypoxia but had no effect on ventilatory variables. It was concluded that amlodipine has the potential to block hypoxic pulmonary vasoconstriction as evidenced by a drug concentration-related decrease in resting tricuspid regurgitation jet velocity without any change in resting myocardial contractility. However, with amlodipine, the subjects felt more breathless during exercise. The reasons for this increase in breathlessness are not clear.
Adult↗
Remifentanil and intubating conditions.
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Anesthetics, Intravenous↗
Evidence of a functional role for the cyclin-dependent kinase inhibitor p21CIP1 in leukemic cell (U937) differentiation induced by low concentrations of 1-beta-D-arabinofuranosylcytosine.
The functional role of the cyclin-dependent kinase inhibitor (CDKI) p21CIP1 in differentiation of human myelomonocytic leukemia cells (U937) exposed to low concentrations of the antimetabolite 1-beta-D-arabino-furanosylcytosine (ara-C) was examined utilizing a cell line stably expressing a p21CIP1 antisense construct. Continuous exposure to 50 nM ara-C led to marked induction of p21CIP1 at 48-72 h in empty-vector control cells but not in their antisense-expressing counterparts (p21AS/F4 and B8). Such treatment induced expression of the myelomonocytic differentiation marker CD11b in approximately 35% of control cells, but no evidence of maturation was noted in antisense-expressing lines. However, antisense-expressing cells exposed to low concentrations of ara-C exhibited a reciprocal increase in apoptosis, manifested by the appearance of cells with classic morphologic features and hypodiploid quantities of DNA, reduced mitochondrial membrane potential (deltapsim), an increase in cytochrome c release into the cytosol, cleavage/activation of procaspases-9 and -3, and degradation of PARP and p27Kip1. Whereas empty-vector control cells exposed to 50 nM ara-C exhibited a decline in Bcl-2 expression, dephosphorylation of pRb, and an initial accumulation in S-phase, antisense-expressing cells did not. However, c-Myc down-regulation induced by low concentrations of ara-C was, if anything, more complete in antisense-expressing cells. Exposure of control but not antisense-expressing cells to ara-C led to phosphorylation/activation of MAP kinase at 24 h; moreover, the specific MEK/MAP kinase inhibitor PD98059 enhanced low-dose ara-C-mediated apoptosis only in wild-type cells. Lastly, exposure to 50 nM ara-C for 72 h resulted in detectable levels of cytoplasmic p21CIP1, a phenomenon associated with resistance to apoptosis, only in empty vector controls. Collectively, these findings demonstrate a functional role for p21CIP1 in leukemic cell maturation induced by low concentrations of ara-C. They also indicate that, as in the case of more conventional differentiation-inducers such as phorbol esters, disruption of the p21CIP1 response after exposure to low concentrations of the cytotoxic drug ara-C prevents leukemic cells from engaging a maturation program, but instead directs them along an apoptotic pathway.
Apoptosis↗
Chronic exposure to bryostatin-1 increases the radiosensitivity of U937 leukaemia cells ectopically expressing Bcl-2 through a non-apoptotic mechanism.
PURPOSE: Ionizing radiation (IR) produced a dose-dependent increase in apoptosis in U937/pCEP4 cells which was attenuated by the stable over expression of Bcl-2 (U937/Bcl-2). A dose of 2 Gy IR was selected for further analyses to determine if subsequent exposure to 10nM bryostatin- would overcome the resistance to IR-induced apoptosis conferred by Bcl-2 over expression. METHODS AND RESULTS: Although bryostatin- did not increase IR-induced apoptosis in U937/pCEP4 or U937/Bcl-2 cells, it impaired mitochondrial function and increased the antiproliferative effects of IR in both cell lines. The effects were more pronounced in U937/Bcl-2 cells. Bryostatin-1 also exerted differential effects on cell-cycle distributions of U937 transfectant cells, producing a significant G0/G1 arrest in U937/Bcl-2 cells, while decreasing IR-induced G2/M arrest in U937/pCEP4 cells. Although Bcl-2 over expression attenuated IR-induced apoptosis, clonogenic survival was similar in U937/pCEP4 and U937/Bcl-2 cells following 2 Gy IR treatment. Treatment with 10nM bryostatin-1 after 2 Gy IR further reduced clonogenic survival in both cell lines. Moreover, U937/Bcl-2 cells were more susceptible to the growth-inhibitory effects of IR/bryostatin-1 than U937/pCEP4 cells. CONCLUSIONS: Bryostatin-1 increased the radiosensitivity of U937 transfectant cell lines without enhancing apoptosis; furthermore, U937/Bcl-2 cells were more susceptible to IR/bryostatin-1-mediated antiproliferative effects than their empty-vector counterparts.
Apoptosis↗
Effects of a 21-day expedition to 6,194 m on human skeletal muscle SR Ca2+-ATPase.
We investigated the effects of a 21-day expedition to the summit of Mount Denali, Alaska (6,194 m) on selected Ca2+ sequestration properties of sarcoplasmic reticulum (SR) calcium pump in vastus lateralis muscle. Muscle samples were obtained by biopsy from 5 male climbers (peak oxygen consumption, VO2peak = 52.3 +/- 2.1 mL.kg(-1).min(-1)) approximately 7 days prior to (PRE) and 4 days following (POST) the expedition. A comparison of PRE versus POST measures of maximal Ca2+-ATPase activities (117 +/- 8.5 vs. 97.6 +/- 5.6 nmol.mg protein(-1).min(-1)) and Ca2+-uptake (204 +/- 15 vs. 161 +/- 11 nmol.mg protein(-1).min(-1)) measured in crude homogenates obtained from pre-exercised muscle, indicated only an effect (p < 0.05) of the expedition on Ca2+-uptake. The reduction in Ca2+-ATPase activity, representing 16.6%, was not significant (p = 0.089). The sarco endoplasmic reticulum calcium (SERCA)-ATPase isoforms, measured using Western blotting techniques, revealed a small reduction (p < 0.05) in SERCA 1 (-4.6 +/- 1.9%), but not in SERCA 2a (+2.0 +/- 1.4%). Prior to the expedition, both Ca2+-ATPase activity and Ca2+-uptake were reduced (p < 0.05) by approximately 34 and 18%, respectively, following 40 min of a two-step continuous cycling task (20 min at 59% VO2peak and 20 min at 74% VO2peak). The exercise-induced reduction in Ca2+-ATPase activity was independent of fiber type. Only in the case of Ca2+-uptake was a lower exercise response (p < 0.05) observed following the expedition, an effect that was due to the lower resting value. It is concluded that acclimatization as experienced during a mountaineering expedition induces changes in the properties of the SR Ca2+-pump, and particularly to Ca2+-sequestering function.
Acclimatization↗
Orbitofrontal cortex and human drug abuse: functional imaging.
The orbitofrontal cortex (OFC) plays a central role in human behavior. Anatomically connected with association areas of all sensory modalities, limbic structures, prefrontal cortical regions that mediate executive function and subcortical nuclei, this brain region can serve to integrate the physical and emotional attributes of a stimulusobject and establish a motivational value based on estimation of potential reward. To the extent that addictive disorders reflect a dysregulation of the ability to evaluate potential reward against harm from drug self-administration, it would be anticipated that substance abuse disorder might reflect dysfunction of the OFC. With the application of brain imaging techniques to the study of human substance abuse, evidence has been obtained that activity in the OFC and its connections plays a role in several components of the maladaptive behavior of substance abuse, including expectancy, craving and impaired decision making.
Frontal Lobe↗
Resting heart rate definition and its effect on apparent levels of physical activity in young children.
PURPOSE: Heart rate monitoring is widely used to measure physical activity in children, but it may be dependent on the definition of resting heart rate used and the protocol used to measure or derive resting heart rate (RHR). The aim of this study was to determine the effect of RHR definition on activity levels assessed by PAHR-25 (% time at >25% of RHR), PAHR-50 (% time at >50% of RHR), and activity heart rate (AHR; mean HR minus RHR). METHODS: Minute-to-minute heart rates were measured over 3 d in 20 healthy preschool children aged 3-4 yr. Resting heart rate was measured for 5 min after a 10-min rest and was also derived from the following different but commonly used protocols: 1) mean of lowest heart rate plus all heart rates within three beats; 2) mean of lowest 5; 3) lowest 10; 4) lowest 50. This gave five different definitions of RHR. Differences in RHR and in the derived indices of activity among definitions were tested for agreement using a Bland-Altman analysis, and by rank order correlation. RESULTS: Differences in RHR among all definitions were statistically significant. These resulted in significant differences in apparent physical activity levels: PAHR-25 varied 10-50% depending on the protocol used to define RHR; PAHR-50 varied by 16-65% as a function of the protocol used to define RHR. However, the different definitions of RHR had no significant influence on physical activity level when children were rank ordered. CONCLUSION: Choice of method for defining RHR has a profound effect on the apparent level of activity of children. This does not alter the relative assessment of activity by rank order. A consensus definition of RHR is desirable if comparisons of activity levels between samples or populations are to be made and if the adequacy of physical activity levels is to be assessed using heart rate.
Body Height↗
National Science Foundation-Sponsored Workshop Report: "The 2010 Project" functional genomics and the virtual plant. A blueprint for understanding how plants are built and how to improve them.
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Genetic Engineering↗
Adaptations in skeletal muscle exercise metabolism to a sustained session of heavy intermittent exercise.
The purpose of this study was to investigate the hypothesis that a single, extended session of heavy exercise would be effective in inducing adaptations in energy metabolism during exercise in the absence of increases in oxidative potential. Ten healthy males [maximal aerobic power (VO(2 peak)) = 43.4 +/- 2.2 (SE) ml x kg(-1) x min(-1)] participated in a 16-h training session involving cycling for 6 min each hour at approximately 90% of maximal oxygen consumption. Measurements of metabolic changes were made on tissue extracted from the vastus lateralis during a two-stage standardized submaximal cycle protocol before (Pre) and 36-48 h after (Post) the training session. At Pre, creatine phosphate (PCr) declined (P < 0.05) by 32% from 0 to 3 min and then remained stable until 20 min of exercise at 60% VO(2 peak) before declining (P < 0.05) by a further 35% during 20 min of exercise at 75% VO(2 peak). Muscle lactate (mmol/kg dry wt) progressively increased (P < 0.05) from 4.59 +/- 0.64 at 0 min to 17.8 +/- 2.7 and 30.9 +/- 5.3 at 3 and 40 min, respectively, whereas muscle glycogen (mmol glucosyl units/kg dry wt) declined (P < 0.05) from a rest value of 360 +/- 24 to 276 +/- 31 and 178 +/- 36 at similar time points. During exercise after the training session, PCr and glycogen were not as depressed (P < 0.05), and increases in muscle lactate were blunted (P < 0.05). All of these changes occurred in the absence of increases in oxidative potential as measured by the maximal activities of citrate synthase and malate dehydrogenase. These findings are consistent with other studies, namely, that muscle metabolic adaptations to regular exercise are an early adaptive event that occurs before increases in oxidative potential.
Adaptation, Physiological↗
Postcontractile force depression in humans is associated with an impairment in SR Ca(2+) pump function.
To investigate the hypothesis that intrinsic changes in sarcoplasmic reticulum (SR) Ca(2+)-sequestration function can be implicated in postcontractile depression (PCD) of force in humans, muscle tissue was obtained from the vastus lateralis and determinations of maximal Ca(2+) uptake and maximal Ca(2+)-ATPase activity were made on homogenates obtained before and after the induction of PCD. Eight untrained females, age 20.6+/-0.75 yr (mean +/- SE), performed a protocol consisting of 30 min of isometric exercise at 60% maximal voluntary contraction and at 50% duty cycle (5-s contraction and 5-s relaxation) to induce PCD. Muscle mechanical performance determined by evoked activation was measured before (0 min), during (15 and 30 min), and after (60 min) exercise. The fatiguing protocol resulted in a progressive reduction (P<0.05) in evoked force, which by 30 min amounted to 52% for low frequency (10 Hz) and 20% for high frequency (100 Hz). No force restoration occurred at either 10 or 100 Hz during a 60-min recovery period. Maximal SR Ca(2+)-ATPase activity (nmol x mg protein(-1) x min(-1)) and maximal SR Ca(2+) uptake (nmol. mg protein(-1) x min(-1)) were depressed (P<0.05) by 15 min of exercise [192+/-45 vs. 114+/-8.7 and 310+/-59 vs. 205+/-47, respectively; mean +/- SE] and remained depressed at 30 min of exercise. No recovery in either measure was observed during the 60-min recovery period. The coupling ratio between Ca(2+)-ATPase and Ca(2+) uptake was preserved throughout exercise and during recovery. These results illustrate that during PCD, Ca(2+) uptake is depressed and that the reduction in Ca(2+) uptake is due to intrinsic alterations in the Ca(2+) pump. The role of altered Ca(2+) sequestration in Ca(2) release, cytosolic-free calcium, and PCD remains to be determined.
Adult↗
Human skeletal muscle exercise metabolism following an expedition to mount denali.
Chronic exposure to high altitude is known to result in changes in the mechanisms regulating O(2) delivery to the contracting muscle. However, the effects of acclimatization on metabolism in the contracting muscle cell remain unclear. In this study, we have investigated the hypothesis that acclimatization would result in a closer coupling between ATP utilization and ATP production and that the improved energy state would be accompanied by a reorganization of the metabolic pathways consisting of an increased oxidative and decreased glycolytic potential. Five men, mean age of 28 +/- 2 (SE) yr, performed a standardized, two-stage submaximal cycling task in normoxia for 20 min at each of 59 and 74% peak O(2) consumption before and 3-4 days after returning from a 21-day expedition to Mount Denali (6,194 m). Acclimatization was without effect in altering the resting values of the adenine nucleotides (ATP, ADP, AMP), inosine monophosphate (IMP), or phosphocreatine (PCr) in the vastus lateralis. During exercise (40 min) after acclimatization compared with preacclimatization, PCr was not as depressed (33.2 +/- 7.1 vs. 40.6 +/- 5.4 mmol/kg dry wt) and IMP (0.289 +/- 0.11 vs. 0. 131 +/- 0.03 mmol/kg dry wt) and lactate (26.1 +/- 6.2 vs. 18.6 +/- 8.8 mmol/kg dry wt) in contracting muscle were not as elevated (P < 0.05). Although no effect of acclimatization was observed for the maximal activity (mol. kg protein(-1). h(-1)) of citrate synthase (4. 76 +/- 0.44 vs. 4.94 +/- 0.45), lactate dehydrogenase was increased by 13% (36.5 +/- 2.6 vs. 41.2 +/- 3.1, P < 0.05). It is concluded that acclimatization results in an improved energy state in the contracting muscle when tested under normoxic conditions; however, these effects are not associated with a higher oxidative potential or a lower glycolytic potential as hypothesized.
Acclimatization↗
Downregulation in muscle Na(+)-K(+)-ATPase following a 21-day expedition to 6,194 m.
To investigate the hypothesis that acclimatization to altitude would result in a downregulation in muscle Na(+)-K(+)-ATPase pump concentration, tissue samples were obtained from the vastus lateralis muscle of six volunteers (5 males and 1 female), ranging in age from 24 to 35 yr, both before and within 3 days after a 21-day expedition to the summit of Mount Denali, Alaska (6,194 m). Na(+)-K(+)-ATPase, measured by the [(3)H]ouabain-binding technique, decreased by 13.8% [348 +/- 12 vs. 300 +/- 7.6 (SE) pmol/g wet wt; P < 0.05]. No changes were found in the maximal activities (mol. kg protein(-1). h(-1)) of the mitochondrial enzymes, succinic dehydrogenase (3.63 +/- 0.20 vs. 3.25 +/- 0.23), citrate synthase (4. 76 +/- 0.44 vs. 4.94 +/- 0.44), and malate dehydrogenase (12.6 +/- 1. 8 vs. 12.7 +/- 1.2). Similarly, the expedition had no effect on any of the histochemical properties examined, namely fiber-type distribution (types I, IIA, IIB, IC, IIC, IIAB), area, capillarization, and succinic dehydrogenase activity. Peak aerobic power (52.3 +/- 2.1 vs. 50.6 +/- 1.9 ml. kg(-1). min(-1)) and body mass (76.9 +/- 3.7 vs. 75.5 +/- 2.9 kg) were also unaffected. We concluded that acclimatization to altitude results in a downregulation in muscle Na(+)-K(+)-ATPase pump concentration, which occurs without changes in oxidative potential and other fiber-type histochemical properties.
3-Hydroxyacyl CoA Dehydrogenases↗
Increases in submaximal cycling efficiency mediated by altitude acclimatization.
To investigate the hypothesis that respiratory gas exchange and, in particular, the O(2) consumption (VO(2)) response to exercise is altered after a 21-day expedition to 6,194 m, five male climbers (age 28.2 +/- 2 yr; weight 76.9 +/- 4.3 kg; means +/- SE) performed a progressive and prolonged two-step cycle test both before and 3-4 days after return to sea level. During both exercise tests, a depression (P < 0.05) in VO(2) (l/min) and an increase (P < 0.05) in minute ventilation (VE BTPS; l/min) and respiratory exchange ratio were observed after the expedition. These changes occurred in the absence of changes in CO(2) production (l/min). During steady-state submaximal exercise, net efficiency, calculated from the rates of the mechanical power output to the energy expended (VO(2)) above that measured at rest, increased (P < 0.05) from 25.9 +/- 1.6 to 31. 3 +/- 1.3% at the lighter power output and from 24.4 +/- 1.3 to 29.5 +/- 1.5% at the heavy power output. These changes were accompanied by a 4.5% reduction (P < 0.05) in peak VO(2) (3.99 +/- 0.17 vs. 3.81 +/- 0.18 l/min). After the expedition, an increase (P < 0.05) in hemoglobin concentration (15.0 +/- 0.49 vs. 15.8 +/- 0.41 g/100 ml) was found. It is concluded that, because resting VO(2) was unchanged, net efficiency is enhanced during submaximal exercise after a mountaineering expedition when the exercise is performed soon after return to sea level conditions.
Acclimatization↗
Signal transduction and cellular radiation responses.
Exposure of cells to ionizing radiation results in complex cellular responses resulting in cell death and altered proliferation states. The underlying cytotoxic, cytoprotective and cellular stress responses to radiation are mediated by existing signaling pathways, activation of which may be amplified by intrinsic cellular radical production systems. These signaling responses include the activation of plasma membrane receptors, the stimulation of cytoplasmic protein kinases, transcriptional activation, and altered cell cycle regulation. From the data presented, there is increasing evidence for the functional links between cellular signal transduction responses and DNA damage recognition and repair, cell survival, or cell death through apoptosis or reproductive mechanisms.
Animals↗
Inhibition of the mitogen activated protein kinase pathway potentiates radiation-induced cell killing via cell cycle arrest at the G2/M transition and independently of increased signaling by the JNK/c-Jun pathway.
The ability of low dose ionizing radiation (2 Gy) to modulate the activities of the mitogen activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK1) cascades in human monocytic leukemia (U937/pREP4) cells and in cells over-expressing dominant negative c-Jun (TAM67) (U937/TAM67) was investigated. Radiation exposure caused prolonged ( approximately 1 h) MAPK activations in U937 cells. In contrast, low dose irradiation weakly modulated JNK1 activity in these cells. Inhibition of the MAPK pathway by use of the specific MEK1/2 inhibitor (10 microM PD98059) in both U937/pREP4 and U937/TAM67 cells prior to radiation exposure permitted strong prolonged radiation-induced activations of JNK1. Expression of TAM67 decreased the ability of radiation to cause apoptosis compared to control transfected cells. However, combined MEK1/2 inhibition and radiation exposure in both cell types caused a large decrease in suspension culture growth and a large increase in apoptosis, when compared to either treatment alone. Reduced proliferation after combined irradiation and PD98059 treatment in both cell types correlated with prolonged cell cycle arrest in G2/M phase. Prolonged growth arrest was abolished when MEK1/2 inhibitor was removed 6 h following irradiation, which was associated with a reduction in apoptosis. The ability of MEK1/2 inhibition to cause prolonged G2/M growth arrest was reduced in U937 cells stably transfected with a p21Cip-1/WAF1 antisense construct (U937/p21AS). This data correlated with an enhancement of radiation-induced apoptosis and a reduced ability of MEK1/2 inhibition to potentiate apoptosis. Collectively our data demonstrate that inhibition of MEK1/2 function increases the radiation sensitivity of U937 cells, independently of c-Jun function, and decreases the ability of these cells to recover from the radiation-induced G2/M cell cycle checkpoint arrest. In addition, our data also demonstrate that the ability of MEK1/2 inhibition to potentiate radiation-induced cell death in U937 cells in part requires an ability of cells to express low levels of p21Cip-1/WAF1.
Apoptosis↗
Follicular dendritic cells protect malignant B cells from apoptosis induced by anti-Fas and antineoplastic agents.
The observation that follicular dendritic cells (FDC) reduce apoptosis in B cells prompted the hypothesis that FDC might enhance tumor cell survival by protecting malignant B cells from apoptotic death. To test this notion, apoptosis was induced in B cell lymphomas by anti-Fas or various antineoplastic agents in the presence and absence of FDC. Apoptosis was detected and quantified by TUNEL analysis. Induction of apoptosis with anti-Fas, etoposide, cyclophosphamide, and busulfan was markedly antagonized by FDC at FDC to B cell ratios of >/=1:16. For example, treatment with 10 ng/ml anti-Fas caused 60-90% of A20 cells to undergo apoptosis in 6 h, whereas addition of FDC reduced apoptosis to background levels (3-15%). Similarly, treatment with busulfan induced apoptosis in 55-80% of A20 cells, whereas addition of FDC reduced B cell death to </=15%; moreover, depletion of FDC abrogated the protective actions. In contrast, the apoptosis-inducing effect of Adriamycin was not reversed by FDC. The ability to block apoptosis induced by anti-Fas or busulfan was not limited to A20 but was observed in four other malignant pre-B cell or B cell lines. The mechanism by which FDC spare malignant B cells from apoptosis did not involve alterations in levels of Bcl-2, Bcl-XL, or Bax. Collectively, these data raise the possibility that FDC may enhance tumor cell survival by protecting malignant B cells against apoptosis induced by anti-Fas and some but not all chemotherapeutic agents.
Animals↗
Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53.
Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.
Apoptosis↗