Etoposide-resistant HT-29 human colon carcinoma cells during glucose deprivation are sensitive to piericidin A, a GRP78 down-regulator.
J Cell Physiol
; 215(1): 243-50, 2008 Apr.
Article
em En
| MEDLINE
| ID: mdl-17941090
ABSTRACT
Glucose deprivation, a pathophysiological cell condition, causes up-regulation of GRP78 and induction of etoposide resistance in human cancer cells. The induction of drug resistance can be partly explained by the fact that GRP78 can block activation of caspase-7 induced by treatment with etoposide. Therefore, downregulating GRP78 expression may be a novel strategy anticancer drug development. Based on that premise, we established a screening program for anticancer agents that exhibit preferential cytotoxic activity for etoposide-resistant cancer cells under glucose-deprived conditions. We recently isolated an active compound, AR-054, from the culture broth of Streptomyces sp., which prevents stress-induced etoposide resistance in vitro. AR-054 was identified as piericidin A, a prototypical compound, by ESI-MS analysis and various NMR spectroscopic methods. Here, we showed that piericidin A suppressed the accumulation of GRP78 protein and was also highly toxic to etoposide-resistant HT-29 cells, with IC50 values for colony formation of 6.4 and 7.7 nM under 2-deoxyglucose supplemented and glucose-deprived conditions, respectively. Interestingly, piericidin A had no effect under normal growth conditions. Therefore, we suggest that piericidin A prevents up-regulation of GRP78, and exhibits cytotoxicity in glucose-deprived HT-29 cells that are resistant to etoposide.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Regulação para Baixo
/
Neoplasias do Colo
/
Chaperonas Moleculares
/
Resistencia a Medicamentos Antineoplásicos
/
Etoposídeo
/
Glucose
/
Proteínas de Choque Térmico
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article