Response to dexamethasone is glucose-sensitive in multiple myeloma cell linesReport as inadecuate




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Journal of Experimental and Clinical Cancer Research

, 30:81

First Online: 13 September 2011Received: 04 May 2011Accepted: 13 September 2011

Abstract

BackgroundHyperglycemia is among the major side effects of dexamethasone DEX. Glucose or glucocorticoid GC regulates the expression of thioredoxin-interacting protein TXNIP that controls the production of reactive oxygen species ROS through the modulation of thioredoxin TRX activity.

MethodsMultiple myeloma MM cells were grown in 5 or 20 mM-L glucose with or without 25 μM DEX. Semiquantitative reverse transcription-PCR RT-PCR was used to assess TXNIP RNA expression in response to glucose and DEX. ROS were detected by 5-6-chloromethyl-2-,7-dichlorodihydrofluorescein diacetate CM-H2DCFDA. TRX activity was assayed by the insulin disulfide-reducing assay. Proliferation was evaluated using CellTiter96 reagent with 490-nm absorbtion and used to calculate the DEX IC50 in 20 mM-L glucose using the Chou-s dose effect equation.

ResultsTXNIP RNA level responded to glucose or DEX with the same order of magnitude ARH77 > NCIH929 > U266B1 in these cells. MC-CAR cells were resistant to the regulation. ROS level increased concurrently with reduced TRX activity. Surprisingly glucose increased TRX activity in MC-CAR cells keeping ROS level low. DEX and glucose were lacking the expected additive effect on TXNIP RNA regulation when used concurrently in sensitive cells. ROS level was significantly lower when DEX was used in conditions of hyperglycemia in ARH77-NCIH9292 cells but not in U266B1 cells. Dex-IC50 increased 10-fold when the dose response effect of DEX was evaluated with glucose in ARH andand and MC-Car cells

ConclusionsOur study shows for the first time that glucose or DEX regulates important components of ROS production through TXNIP modulation or direct interference with TRX activity in MM cells. We show that glucose modulates the activity of DEX through ROS regualtion in MM cells. A better understanding of these pathways may help in improving the efficacy and reducing the toxicity of DEX, a drug still highly used in the treatment of MM. Our study also set the ground to study the relevance of the metabolic milieu in affecting drug response and toxicity in diabetic versus non-diabetic patients with MM.

AbbreviationsDEXdexamethasone

GCglucocorticoid

TXNIPthioredoxin interacting protein

TRXthioredoxin

MMmultiple myeloma

IMDsimmune modulator drugs

RT-PCRreverse transcriptase polymerase chain reaction

CM-H2DCFDA5-6 chloromehtyk-2-7-dichloridihydrofluorescien diacetate

ROSreactive oxygen species

ChoREcarbohydrate responsive elements

GC-REglucocorticoid responsive element

IC50inhibitory concentration 50%.

Electronic supplementary materialThe online version of this article doi:10.1186-1756-9966-30-81 contains supplementary material, which is available to authorized users.

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Author: Ellen Friday - Johnathan Ledet - Francesco Turturro

Source: https://link.springer.com/



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