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At least 757 records · Page 42Linked to original sources
PubMed1992

Cholera toxin-sensitive 3',5'-cyclic adenosine monophosphate and calcium signals of the human dopamine-D1 receptor: selective potentiation by protein kinase A.

The signal transduction pathways of the dopamine-D1 receptor were investigated in two cell types stably transfected with the human D1 receptor cDNA, rat pituitary GH4C1 cells (GH4-hD1), and mouse Ltk-fibroblast cells (L-hD1). In both GH4-hD1 and L-hD1 cell lines, stimulation of the dopamine-D1 receptor induced a marked increase in cAMP accumulation. In addition, dopamine potentiated activation of L-type voltage-dependent calcium channels in a cAMP-dependent manner in GH4-hD1 cells. However, in L-hD1 cells, dopamine increased cytosolic free calcium concentrations ([Ca++]i) by mobilization of intracellular calcium rather than by calcium influx. This effect was correlated with a dopamine-induced enhancement of phospholipase C activity in L-hD1 cells. Pretreatment (24 h) with cholera toxin (CTX) was used to maximally activate the GTP-binding protein (G protein) Gs, causing a maximal elevation of cAMP levels and uncoupling the D1 receptor from Gs. The described actions of dopamine in both cell lines were abolished by pretreatment with CTX, indicating that CTX substrates (e.g. Gs) may mediate these actions. The blockade by CTX was not due to CTX-induced elevation of cAMP, since pretreatment with forskolin or 8-bromo-cAMP to activate cAMP-dependent protein kinase did not inhibit dopamine actions nor alter basal [Ca++]i. Pretreatment (1-3 h) of L-hD1 cells with forskolin (10 microM) or 8-bromo-cAMP (5 mM) altered neither the basal activity of phospholipase C nor basal [Ca++]i in L-hD1 cells but greatly enhanced the dopamine-induced increase of phosphatidyl inositol turnover and [Ca++]i. From these results we conclude that: 1) the dopamine-D1 receptor induces multiple and cell-specific signals, including elevation of cAMP levels in both GH and L cells, cAMP-dependent activation and potentiation of opening of L-type voltage-dependent calcium channel in GH cells, and a novel phosphatidyl inositol-linked mobilization of cellular calcium in L cells; 2) coupling of the D1 receptor to these responses involves CTX-sensitive proteins, possibly Gs; and 3) acute preactivation of cAMP-dependent protein kinase can markedly enhance, rather than attenuate, certain pathways of dopamine-D1 transmembrane signaling.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Mild hypothermia and MK-801 have similar but not additive degrees of cerebroprotection in the rat permanent focal ischemia model.

Although not the sole factor, glutamate-mediated excitotoxicity is accepted as a major mechanism of ischemic neuronal damage. MK-801 and mild hypothermia, two cerebroprotective modalities, which have been documented to alter glutamatergic action, were tested in the rat middle cerebral artery occlusion (MCAO) model simulating permanent focal ischemia. We administered normothermic (37 degrees C) animals with either MK-801 (1.0 mg/kg 30 min before MCAO or 2.5 mg/kg 30 min before, immediately after, 4 hours, and 8 hours after MCAO) or saline vehicle (30 min before MCAO). Mildly hypothermic (33 degrees C) animals were administered either MK-801 (1.0 mg/kg) or saline vehicle 30 minutes before MCAO. Mild hypothermia was induced over a 20-minute period before MCAO in hypothermic animals. All animals were killed 24 hours after MCAO; their brains were sectioned and stained with 2,3,5-triphenyltetrazolium chloride and their infarct volumes were calculated. In normothermica animals given 1.0 mg/kg and multidose 2.5-mg/kg intraperitoneal injections of MK-801, the infarct volumes (as a percentage of right hemispheric volume) were 16.8 +/- 3.5% and 16.3 +/- 3.0%, respectively. These infarct volumes were significantly different (P < 0.05; single-variable analysis of variance) from the normothermic, drug-free control (26.8 +/- 1.9%), but not significantly different from each other. Analysis of the data using a nonparametric test (Kruskal-Wallis; P = 0.02) confirmed the same significant differences in infarct size. The infarct volumes from the mildly hypothermic groups were not different (1 mg/kg of MK-801, 15.5 +/- 2.3% and saline control, 15.4 +/- 1.1%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Left ventricular pump function in right ventricular overload.

To clarify how left ventricular pumping action is altered in cor pulmonale, an experimental study was performed using canine heart preparations in which the effects on left ventricular performance of right ventricular overload, with and without depressed systolic function, were investigated. For this purpose, two methods using excised perfused hearts (n = 16) and in vivo hearts (n = 6) were employed, and in the latter condition, pulmonary artery constriction (n = 7), femoral arterial-venous (A-V) shunt (n = 3) and right coronary artery occlusion (n = 6) were induced. Left ventricular systolic function was assessed by the relationship between left ventricular isovolumic developed pressure and left ventricular volume in excised heart, and by ejection fraction with 2 dimensional echocardiogram in the vivo condition, taking into account preload and afterload changes. From the excised heart preparation, it was shown that left ventricular developed pressure significantly decreases when right and left ventricular diastolic pressure increases greatly. On the other hand, in vivo right ventricular overload due to pulmonary constriction and A-V shunt, the left ventricular ejection fraction increased following afterload reduction. When we compare the left ventricular ejection fraction in pulmonary constriction with that in right coronary occlusion, in which reduction of left ventricular diastolic area from the control was similar, the latter was significantly decreased despite afterload reduction. These results suggest that right ventricular overload does not necessarily induce left ventricular systolic dysfunction unless left ventricular end-diastolic pressure, as well as that of the right ventricle, increases definitely and simultaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

The endothelin antagonist bosentan does not improve survival in severe experimental pancreatitis in rats.

BACKGROUND: Severity of pancreatitis seems to be aggravated by impairment of vascular perfusion of the gland. Early mortality occurs within the first few days from the acute consequences of pancreatic injury with subsequent inflammatory response. Because vasoactive substances, including endothelin, seem to contribute to early mortality in acute pancreatitis, we tested the hypothesis that the inhibition of endothelin action could alter the outcome after severe experimental pancreatitis. METHODS: In two groups of rats, pancreatitis was induced by intraductal infusion into the pancreatic duct of 1 microL/g body weight (b.w.) of either a 4% or a 5% sodium taurocholate solution. The mixed endothelin A and endothelin B receptor antagonist bosentan (20 mg/kg b.w.) or vehicle was injected intravenously in 12-h intervals for 3 d starting 1 h after induction of bile acid pancreatitis. This dose of bosentan is known to completely inhibit the effect of exogenous endothelin. The survival rate was monitored for 7 d. Thereafter, the surviving rats were sacrificed and the pancreas was prepared for histological and biochemical evaluation. RESULTS: Irrespective of the treatment protocol (bosentan versus saline), survival was not different in animals challenged with either 4% or 5% sodium taurocholate. The corresponding survival rates were 62% with bosentan and 77% without bosentan in the 4% sodium taurocholate group. In the 5% sodium taurocholate group, the survival rates were 20% with and 27% without bosentan. Morphological and biochemical alterations were identical in control as well as in endothelin-antagonist-treated rats. CONCLUSION: Therapy with the mixed endothelin A and endothelin B receptor antagonist bosentan does not influence the outcome after severe experimental pancreatitis. Therefore, blockade of endothelin A and B receptor subtypes may not be of major importance as a therapeutic principle in this model of experimental pancreatitis.

Animals↗
PubMed1995

Effect of alpha 2-adrenergic agonist clonidine on plasma growth hormone and insulin-like growth factor-I concentrations in barrows.

The effects of infusion of clonidine, an alpha2-adrenergic agonist, on plasma insulin-like growth factor-I (IGF-I) concentrations were investigated with a single growth hormone (GH) injection in pigs. Four barrows were subjected to four treatments: saline infusion with a vehicle injection, clonidine infusion (0.5 nmol/kg/min for 8 h) with a vehicle injection, saline infusion with a bovine GH (bGH: 100 micrograms/kg) injection, and clonidine infusion with a bGH injection. Infusion was started 1 h before the injection. Plasma IGF-I, bGH, porcine GH (pGH), insulin, glucose, non-esterified fatty acid (NEFA), and blood urea nitrogen (BUN) concentrations were measured. Plasma IGF-I concentrations during saline infusion increased after a bGH injection (P < 0.05). However, the IGF-I concentrations during clonidine infusion did not increase after the bGH injection. Plasma endogenous GH (pGH) was not increased during clonidine infusion. The plasma glucose concentration was noticeably increased during clonidine infusion and moderately increased after the GH injection. Despite the extreme increase in plasma glucose during clonidine infusion, plasma insulin did not change. Neither plasma NEFA nor BUN was changed by these treatments. These results demonstrate that the alpha 2-adrenergic agonist clonidine altered the action of GH to increase the plasma IGF-I concentrations.

Adrenergic alpha-Agonists↗
PubMed2005

Large-conductance calcium-activated potassium channels facilitate transmitter release in salamander rod synapse.

Large-conductance calcium-activated potassium (BK) channels are colocalized with calcium channels at sites of exocytosis at the presynaptic terminals throughout the nervous system. It is expected that their activation would provide negative feedback to transmitter release, but the opposite is sometimes observed. Attempts to resolve this apparent paradox based on alterations in action potential waveform have been ambiguous. In an alternative approach, we investigated the influence of this channel on neurotransmitter release in a nonspiking neuron, the salamander rod photoreceptors. Surprisingly, the BK channel facilitates calcium-mediated transmitter release from rods. The two presynaptic channels form a positive coupled loop. Calcium influx activates the BK channel current, leading to potassium efflux that increases the calcium current. The normal physiological voltage range of the rod is well matched to the dynamics of this positive loop. When the rod is further depolarized, then the hyperpolarizing BK channel current exceeds its facilitatory effect, causing truncation of transmitter release. Thus, the calcium channel-BK channel linkage performs two functions at the synapse: nonlinear potentiator and safety brake.

Action Potentials↗
PubMed2026

PSIP1::TBL1X: a recurrent gene fusion in pancreatic neuroendocrine tumors.

Effective treatment of metastatic neuroendocrine tumors (NETs) is limited by a lack of targeted therapies and clinically useful predictive biomarkers. We applied complementary genomic profiling technologies, including optical genome mapping (OGM) and whole exome sequencing (WES), to 70 liver metastases of NETs from multiple anatomical primary sites to identify actionable genomic alterations. We detected recurrent fusions involving TBL1X (PSIP1::TBL1X) and BEND2 (CHD7::BEND2 and NEO1::BEND2) by OGM in pancreatic neuroendocrine tumors (pNETs). The expression of the PSIP1::TBL1X fusion was confirmed by PacBio Iso-Seq long-read transcriptome sequencing and nested rtPCR, and fusion protein expression was established by western blotting. Expression of the PSIP1::TBL1X fusion was also assayed in a separate cohort of 31 specimens from 28 pNET cases by rtPCR. Across both cohorts, PSIP1::TBL1X was identified in 11% of pNET patients with available metastatic tissue, but was not detected in primary tumor specimens. All PSIP1::TBL1X fusion isoforms were found to retain early exons of PSIP1 and the complete coding sequence of TBL1X. Consistent with prior reports, BEND2 fusions were associated with high-grade tumors and may represent a clinically useful biomarker for aggressive disease. Notably, TBL1X and BEND2 fusions did not co-occur with ATRX/DAXX mutations, defining a distinct molecular subgroup of pNETs. This study highlights the importance of structural variant profiling in molecular profiling studies and supports a revised view of the role of gene fusions in neuroendocrine malignancies.

Humans↗
PubMed2002

EPO's alter ego: erythropoietin has multiple actions.

Many cancer patients suffer from anemia, which has a major detrimental effect on their quality of life. Recombinant human erythropoietin (rHuEPO) is now widely used in cancer patients, as it improves hematocrit, lowers blood transfusion requirements, and improves quality of life. Recent research indicates that EPO has pleiotropic effects on the body well beyond the maintenance of red cell mass, but the mechanisms involved in relieving fatigue and improving quality of life in cancer patients are poorly understood. EPO receptors (EPO-Rs) have been detected in many different cells and tissues, providing evidence for autocrine, paracrine, and endocrine functions of EPO. Apart from its endocrine function, EPO may have a generalized role as an antiapoptotic agent that is associated with enhancement of muscle tone, mucosal status, and gonadal and cognitive function. The recent discovery of EPO-Rs in breast tumor vasculature, while raising important questions about the possible effects of pharmacological doses of rHuEPO on tumor cells, also suggests that the receptors could provide a useful target for drugs attached to EPO.

Anemia↗
PubMed1988

Mechanism of action of cyclic AMP in altering steroid metabolism in permeabilized rat hepatocytes.

The effects of various concentrations of cyclic AMP (cAMP) on the metabolism of androst-4-ene-3,17-dione were examined in electropermeabilized rat hepatocytes. cAMP had a biphasic effect on hepatic steroid metabolism which was dependent upon both concentration and time. At low concentrations (50 microM) early (1 h) inhibitory effects predominated, whereas at higher concentrations (5 mM) later (2-3 h) stimulatory effects were seen. The use of selective protein kinase inhibitors indicated that all the effects of cAMP were mediated through activation of protein kinase A, but that the inhibitory response also involved activation of protein kinase C. The stimulatory effect was blocked by cycloheximide, indicating that protein synthesis is necessary for this response. These findings help to elucidate the mechanisms by which hormones and other compounds may give their effects on hepatic steroid metabolism and indicate a possibly novel interaction of cAMP and protein kinase C.

Androstenedione↗
PubMed1997

Drug interactions with grapefruit juice.

Some drugs demonstrate a significantly greater (up to 3-fold) mean oral bioavailability on coadministration with grapefruit juice. With some calcium antagonists, the benzodiazepines midazolam and triazolam and the antihistamine terfenadine, changes in bioavailability are accompanied by altered drug action. Study design factors possibly contribute to the magnitude of changes in drug bioavailability; they include the source of the citrus, its intake schedule, drug formulations and individual metabolising capacity. The components of citrus juice that are responsible for clinical drug interactions have yet to be fully determined. Based on the flavonoid naringin's unique distribution in the plant kingdom, abundance in grapefruit and ability to inhibit metabolic enzymes, naringin is likely to be one of the grapefruit components influencing drug metabolism. Other components present in citrus fruit, such as furanocoumarins, may be more potent inhibitors than flavonoids and are under investigation. Conclusions drawn from clinical drug interaction studies should be considered specific to the citrus fruit products evaluated because of the variation in their natural product content. The predominant mechanism for enhanced bioavailability is presumably the inhibition of oxidative drug metabolism in the small intestine. The consistent findings across studies of diverse cytochrome P450 (CYP) 3A substrates support the mechanistic hypothesis that 1 or more grapefruit juice components inhibit CYP3A enzymes in the gastrointestinal tract. The evaluation of the need to avoid the concomitant intake of grapefruit products with drugs is best done on an individual drug basis rather than collectively by drug class. Based on the narrow therapeutic range of cyclosporin and research experience in organ transplant recipients, its interaction with grapefruit juice is likely to be clinically significant.

Anti-Anxiety Agents↗
PubMed2005

Oncogenes as novel targets for cancer therapy (part IV): regulators of the cell cycle and apoptosis.

This is the final part of a four-part serial review on oncogenes and their potential use as targets for cancer therapy. Previous sections discussed various categories of oncogenes (growth factors, tyrosine kinases, intermediate signaling molecules, and transcription factors) and the advances made in various strategies being used to alter their actions. This part describes four oncogenes, MDM2, BCL2, XIAP, and Survivin, that are involved in regulation of the cell cycle and apoptosis.

Animals↗
PubMed2005

Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus.

Glucose directly alters the action potential frequency of glucosensing neurons in the ventromedial hypothalamic nucleus (VMN). Glucose-excited neurons increase, and glucose-inhibited neurons decrease, their action potential frequency as glucose increases from 0.1 to 2.5 mmol/l. Glucose-excited neurons utilize the ATP-sensitive K(+) channel (K(ATP) channel) to sense glucose, whereas glucose opens a chloride channel in glucose-inhibited neurons. We tested the hypothesis that lactate, an alternate energy substrate, also regulates the action potential frequency of VMN glucose-excited and -inhibited but not nonglucosensing neurons. As expected, lactate reversed the inhibitory effects of decreased glucose on VMN glucose-excited neurons via closure of the K(ATP) channel. Although increasing glucose from 2.5 to 5 mmol/l did not affect the activity of glucose-excited neurons, the addition of 0.5 mmol/l lactate or the K(ATP) channel blocker tolbutamide increased their action potential frequency. In contrast to the glucose-excited neurons, lactate did not reverse the effects of decreased glucose on VMN glucose-inhibited neurons. In fact, it increased their action potential frequency in both low and 2.5 mmol/l glucose. This effect was mediated by both K(ATP) and chloride channels. Nonglucosensing neurons were not affected by lactate. Thus, glucose and lactate have similar effects on VMN glucose-excited neurons, but they have opposing effects on VMN glucose-inhibited neurons.

Animals↗
PubMed2001

Effect of dietary modification of muscle long-chain n-3 fatty acid on plasma insulin and lipid metabolites, carcass traits, and fat deposition in lambs.

In a previous study we showed that feeding fish meal significantly increased muscle long chain n-3 fatty acids (FA) and hot carcass weight. In this study we compared the effect of fish meal and fish oil on increasing muscle long-chain FA. We also investigated whether the increase in carcass weight was due to the effect of dietary enrichment of muscle long-chain n-3 FA on muscle membrane phospholipids and(or) to rumen by-pass protein provided by fish meal. Forty crossbred ([Merino x Border Leicester] x Poll Dorset) wether lambs between 26 and 33 kg BW were randomly assigned to one of five treatments: 1) basal diet of oaten:lucerne chaff (Basal); 2) Basal + fish meal (9% DM) = FM; 3) Basal + fish oil (1.5% DM) with protected sunflower meal (9% DM ) = FOSMP; 4) Basal + fish oil (1.5% DM) = FO; or 5) Basal + protected sunflower meal (10.5% DM) = SMP. Daily intake of ME (9.60 - 10.5 MJ ME/d) and CP (150 to 168 g/d) in all treatments was kept similar by varying the ratio of oaten:lucerne chaff and by feeding the animals at 90% ad libitum intake. Blood samples were collected at the start of the experiment and on the day (d 42) prior to slaughter. Lambs were then slaughtered at a commercial abattoir. At 24 h postmortem carcass traits were measured and longissimus thoracis muscle taken for analysis of FA of phospholipid and triglyceride fractions. Lambs fed FO and FOSMP showed a marked increase in muscle longchain n-3 FA (P < 0.001) and a reduction in magnitude of the rise in insulin concentration (P < 0.001) after feeding compared with lambs fed Basal and SMP diets. Lambs in FM had a moderate increase (P < 0.001) in muscle long-chain n-3 FA content. Compared with Basal diet, both plasma total cholesterol (P < 0.02) and high-density lipoprotein cholesterol (P < 0.001) levels were greater in SMP and less in FO and FOSMP treatments. The i.m. fat content was reduced (P < 0.05) in FM and FO treatments, but carcass weight was increased only with fish meal (P < 0.03). Adding SMP to FO produced muscle with an intermediate level of i.m. fat, whereas muscle long-chain n-3 FA, i.m. fat, and insulin concentration were unchanged with SMP treatment. These results indicate that an increase in carcass weight in FM may be due to the supply of ruminally undegraded protein. They also suggest that fish oil along with fish meal can increase long-chain n-3 FA content in phospholipid of muscle membrane. This may be associated with reduced i.m. fat content and altered insulin action and lipoprotein metabolism.

Adipose Tissue↗
PubMed1985

Thirteen cationic ionophores: their acute toxicity, neurobehavioral and membrane effects.

Thirteen cationic ionophores (12-Crown-4, 15-Crown-5, 18-Crown-6, Dibenzo 18-Crown-6, Dicyclohexano 18-Crown-6, 24-Crown-8, Dicyclohexano 24-Crown-8, Lasalocid, Hexacyclen trisulfate, Chiral binapthol, Valinomycin, Monensin, and A-23187) were evaluated for acute toxicologic properties, including lethality and neurobehavioral effects in multiple species (rats, rabbits, and mice) by multiple routes, skin and eye irritation and effects on membrane permeability to physiologic cations. Attention was focused on determining minimum neurobehavioral effect levels and characterizing the spectrum of these effects at different dose levels. While LD50's followed one pattern, this was not the case with other effects. Cluster and factor analysis suggest that, though the primary mechanism of action is alteration of membrane permeability to specifi-cations (qualitative types of activity correlate with the results of membrane permeability studies), which ions are provided an increased passage varies with ring size and charge dispersion. In the intact animal absorption markedly modifies these results.

Animals↗
PubMed2026

Genomic instability, postoperative recurrence and therapeutic vulnerabilities in resectable non&#x2011;small cell lung cancer (Review).

Resectable non&#x2011;small cell lung cancer (NSCLC) is managed largely according to anatomical stage, pathological risk and actionable driver alterations, yet these factors do not fully explain postoperative recurrence. Genomic instability may contribute to recurrence by promoting clonal diversification, intratumoral heterogeneity, occult dissemination, persistence of residual tumor cells, and immune escape. In the present review, chromosomal instability (CIN), copy&#x2011;number complexity, whole&#x2011;genome doubling, DNA repair defects, replication stress, and extrachromosomal DNA (ecDNA) were critically evaluated using a three&#x2011;axis translational framework encompassing biological consequences, potential clinical roles, and strength of evidence. Current evidence suggests that clonal diversity and copy&#x2011;number complexity have the clearest near&#x2011;term prognostic rationale. By contrast, CIN and whole&#x2011;genome doubling are supported more strongly by evolutionary and mechanistic rather than prospective clinical evidence. Defects in DNA repair, replication stress, and ecDNA represent potential therapeutic vulnerabilities, but their clinical relevance remains to be established. To date, no treatment&#x2011;predictive biomarkers based on genomic instability have been identified for resectable NSCLC. Direct clinical evidence linking any specific genomic instability feature to the presence or longitudinal dynamics of postoperative molecular residual disease (MRD) remains limited. Postoperative circulating tumor DNA&#x2011;defined MRD provides prognostic information more directly related to residual disease but remains assay&#x2011;dependent and should not be considered a genomic&#x2011;instability phenotype. Therefore, features of genomic instability should remain investigational and should not replace established clinical, pathological, or molecular decision&#x2011;making. Their near&#x2011;term value lies in refining biological risk models and generating testable hypotheses for biomarker&#x2011;defined perioperative trials.

Humans↗
PubMed2001

Detecting and reducing hospital adverse events: outcomes of the Wimmera clinical risk management program.

OBJECTIVES: To determine if an integrated clinical risk management program that detects adverse patient events in a hospital, analyses their risk and takes action can alter the rate of adverse events. DESIGN: Longitudinal survey of adverse patient events over eight years of progressive implementation of the risk management program. PARTICIPANTS AND SETTING: 49,834 inpatients (July 1991 to September 1999) and 20,050 emergency department patients (October 1997 to September 1999) at a rural base hospital in the Wimmera region of Victoria. MAIN OUTCOME MEASURES: Rates of adverse events detected by medical record review and clinical incident and general practitioner reporting. RESULTS: The annual rate of inpatient adverse events decreased between the first and eighth years of the study from 1.35% of all patient discharges (69 events) to 0.74% (49 events) (P<0.001). Absolute risk reduction was 0.61% (95% CI, 0.23%-0.99%), and relative risk reduction was 44.9% (95% CI, 16.9%-72.9%). The quarterly rate of emergency department adverse events decreased between the first and eighth quarters of monitoring from 3.26% of all attendances (84 events) to 0.48% (12 events) (P< 0.001). Absolute risk reduction was 2.78% (95% CI, 2.04%-3.52%), and relative risk reduction was 85.3% (95% CI, 62.7%-100%). CONCLUSIONS: Adverse patient events can be detected, and their frequency reduced, using multiple detection methods and clinical improvement strategies as part of an integrated clinical risk management program.

Clinical Competence↗
PubMed1999

Drug resistance in multiple myeloma: approaches to circumvention.

Resistance mechanisms to chemotherapy in multiple myeloma include (1) reduced drug concentrations at the target site of action, (2) alterations in the drug target, and (3) inhibition or prevention of drug-induced apoptosis. Recent advances in understanding resistance mechanisms have resulted in the investigation of novel therapies for the treatment of patients with multiple myeloma. P-glycoprotein is a drug transport protein that decreases intracellular drug concentrations at the target site. Valspodar, a third-generation cyclosporine analog, is an inhibitor of P-glycoprotein that currently is being evaluated to potentially overcome this mechanism of drug resistance. P-glycoprotein inhibitors (also known as chemosensitizers) are being investigated for use in combination with chemotherapeutic agents to enhance the apoptotic effect and prevent resistance at the target site. Other novel approaches involve blocking pathways that result in the expression of antiapoptosis factors. Interleukin-6 is an important growth factor in myeloma and has been implicated in drug resistance via an antiapoptosis effect. In vitro blocking of an interleukin-6-dependent pathway with either a JAK inhibitor (tyrphostin, AG490) or STAT3 dominant negative (STAT3-DN) reduced expression of Bcl-xL (an antiapoptosis protein), increased spontaneous apoptosis, and enhanced sensitivity to Fas-mediated apoptosis. In conclusion, several cellular mechanisms reduce the response to drug therapy in multiple myeloma. Future treatment approaches for this condition most likely will involve combinations of agents to enhance response or prevent resistance.

ATP Binding Cassette Transporter, Subfamily B↗