Use of NQO1 status as a selective biomarker for oesophageal squamous cell carcinomas with greater sensitivity to 17-AAGReportar como inadecuado




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BMC Cancer

, 14:334

Cell and molecular biology

Abstract

BackgroundOesophageal squamous cell carcinoma OSCC is a major health burden in Sub-Saharan Africa, and novel chemotherapies are urgently required to combat this disease. The heat shock protein 90 HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin 17-AAG has previously been proposed as a possible candidate drug. NADPH quinone oxidoreductase 1 NQO1 is known to increase the potency of 17-AAG, therefore we investigated the effects of 17-AAG in OSCC cell lines in the context of their NQO1 status.

MethodsWe used MTT assays to compare the sensitivity of a panel of OSCC cell lines to 17-AAG. Western blotting, and RT-PCR were used to investigate NQO1 protein and mRNA levels, while an RFLP approach was used to investigate the NQO1 C609T SNP.

ResultsExpression of NQO1 markedly increased sensitivity to 17-AAG in the OSCC cell lines, while normal fibroblasts, which expressed HSP90 at much lower levels, were more resistant to 17-AAG. In isolation, neither the C609T SNP, nor NQO1 mRNA levels was an accurate predictor of NQO1 protein levels.

ConclusionsSince NQO1 greatly enhances the anti-cancer effects of 17-AAG, this could be used as a selective marker for patients that would benefit most from 17-AAG chemotherapy at low doses. Testing for the presence of the C609T SNP in both alleles could be used as a screen to exclude potentially poor responders to 17-AAG treatment at low dosages.

Abbreviations17-AAG17-N-allylamino-17-demethoxygeldanamycin

BABenzoquinone ansamycin

EGFREpidermal growth factor receptor

HSP90Heat shock protein 90

FADFlavin adenine dinucleotide

IGF-1RInsulin-like growth factor 1 receptor

MTT3-4, 5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide

NQO1NAP P H: quinone oxidoreductase 1

OSCCOesophageal squamous cell carcinoma

PARPPoly ADP ribose polymerase

RT-PCRReal time polymerase chain reaction

RFLPRestriction fragment length polymorphism

SNPSingle nucleotide polymorphism.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-334 contains supplementary material, which is available to authorized users.

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Autor: Katie E Hadley - Denver T Hendricks

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







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