Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1.
Cancer Biol Ther
; 7(3): 468-75, 2008 Mar.
Article
em En
| MEDLINE
| ID: mdl-18285700
ABSTRACT
The intrinsic or acquired resistance to multiple drugs (MDR) of cancer cells remains one of the main obstacles for chemotherapy. Development of small molecule targeting to hypoxia inducible factor-1 (HIF-1) has been recently proposed as strategy for treatments of drug-resistant solid tumors. In the present study, emodin, proven as a reactive oxygen species (ROS) generator by our previous work, was applied in combination with cisplatin and other chemotherapeutic drugs in the multidrug resistant prostate carcinoma cell line DU-145 and normal human dermal fibroblasts. Results showed that emodin/cisplatin co-treatment remarkably elevated ROS level and enhanced chemosensitivity in DU-145 cells, compared with cisplatin-only treatment, but exerted little effect on non-tumor cells. The effect of co-treatment on MDR1 gene and its upstream regulator HIF-1 was then investigated in DU-145. Co-treatment downregulated MDR1 expression and promoted drug retention, and meanwhile suppressed transactivation of HIF-1 in response to hypoxia without changing expression of HIF-1 alpha. The experiments on tumor-bearing mice showed that co-treatment inhibited the tumor growth in vivo, owing to oxidative stress and MDR1 down-regulation within tumors. HIF-1 transactivation and clonegenesis were suppressed in cells isolated from the tumors. Finally, examinations for the body weight, the organ histology and the antioxidant capacity of serum suggested that no systemic toxicity related to co-treatment was discernable. In conclusions, emodin, as a novel small inhibitor of HIF-1, may be recognized an effective adjunctive to improve efficacy of cytotoxic drugs in prostate cancer cells with over-activated HIF-1 and potent MDR.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Sobrevivência Celular
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Emodina
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Espécies Reativas de Oxigênio
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Resistência a Múltiplos Medicamentos
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Inibidores de Proteínas Quinases
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Fator 1 Induzível por Hipóxia
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Antineoplásicos
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article