Sulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patientsReportar como inadecuado




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Cancer Cell International

, 4:4

First Online: 17 May 2004Received: 19 December 2003Accepted: 17 May 2004

Abstract

BackgroundMalignant peripheral nerve sheath tumors MPNSTs are neoplasms leading to death in most cases. Patients with Neurofibromatosis type 1 have an increased risk of developing this malignancy. The metabolites of the inactive prodrug Sulindac, Sulindac Sulfide and Sulindac Sulfone Exisulind are new chemopreventive agents that show promising results in the treatment of different cancer types. In this study we examined the antineoplastic effect of these compounds on primary cells derived from two MPNSTs of Neurofibromatosis type 1 patients.

ResultsExisulind and Sulindac Sulfide showed a dramatic time- and dose-dependent growth inhibitory effect with IC50-values of 120 μM and 63 μM, respectively. The decrease in viability of the tested cells correlated with induction of apoptosis. Treatment with 500 μM Exisulind and 125 μM Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells. Reduced expression of RAS-GTP and phosphorylated ERK1-2 was detected in treated MPNST cells. Moreover, elevated levels of phosphorylated SAPK-JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen.

ConclusionsOur results suggest that this class of compounds may be of therapeutic benefit for Neurofibromatosis type 1 patients with MPNST.

List of abbreviationsMPNSTmalignant peripheral nerve sheath tumor

NF1neurofibromatosis type 1

FAPfamilial adenomatous polyposis

NSAIDnonsteroidal anti-inflammatory drug

COXcyclooxigenase

PDEphosphodiesterase

PKGproteinkinase G

JNKC-jun N-terminal protein kinase

MEKKmitogen activated protein kinase kinase kinase

PARPpoly ADP-ribose polymerase

phospho-ERK1-2phosphorylated extracellular signal-regulated kinase 1 and 2

NIHnational institute of health

DMEMDulbecco-s modified eagle medium

FBSfetal bovine serum

DMSOdimethyl sulfoxide

BrdU5-Bromo-2-deoxyuridine

bFGFbasic fibroblastic growth factor

PBSphosphate buffered saline

XTTsodium 3-1-phenylaminocarbonyl-3,4-tetrazolium-bis4-methoxy-6-nitrobenzene sulfonic acid hydrate

TUNELterminal deoxynucleotidyltransferase dUTP nick end labelling

PIpropidium iodide

TBSTris-buffered normal saline

EGFepidermal growth factor

DTTdithiothreitol

PMSFphenylmethylsulfonyl fluoride

DHAdocosahexaenoic acid

SAPKstress-activated protein kinase

hhours.

Electronic supplementary materialThe online version of this article doi:10.1186-1475-2867-4-4 contains supplementary material, which is available to authorized users.

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Autor: Silke Frahm - Andreas Kurtz - Lan Kluwe - Faris Farassati - Reinhard E Friedrich - Victor F Mautner

Fuente: https://link.springer.com/







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