Enhancement of docetaxel-induced cytotoxicity and apoptosis by all-trans retinoic acid ATRA through downregulation of survivin BIRC5, MCL-1 and LTbeta-R in hormone- and drug resistant prostate cancer cell line, DU-145Reportar como inadecuado




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Journal of Experimental and Clinical Cancer Research

, 27:37

First Online: 12 September 2008Received: 29 July 2008Accepted: 12 September 2008

Abstract

BackgroundThe management of hormone-refractory prostate cancer HRPC still remains as an important challenge of daily oncology practice. Docetaxel has proved to be a first line treatment choice. All-trans retinoic acid ATRA could potently inhibit the growth of prostate cancer cells in vitro and its combination with various anticancer agents results in increased cytotoxicity. Based on these data, our aim was to examine the synergistic-additive cytotoxic and apoptotic effects of combination of docetaxel and ATRA, in hormone- and drug refractory human DU-145 prostate cancer cells. Furthermore, we have searched for the underlying mechanisms of apoptosis by demonstrating apoptosis-related genes.

MethodsXTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3-7 activity measurement were used. For detecting the mechanism of apoptosis induced by docetaxel-ATRA combination, OligoGeArray which consists of 112 apoptosis related genes was used.

ResultsOur results revealed that docetaxel and ATRA were synergistically cytotoxic and apoptotic in DU-145 cells, in a dose- and time dependent manner. It was also shown by our studies that apoptosis was induced in DU-145 prostate carcinoma cells with significant cytotoxicity, no matter which agent applied first. We have found out that docetaxel-ATRA combination significantly downregulates survivin BIRC5, myeloid cell leukemia-1 MCL-1 and lymphotoxin β-receptor LTβR genes, which all three have pivotal roles in regulation of apoptosis and cell cycle progression.

ConclusionIn conclusion, we strongly suggest that docetaxel and ATRA combination is a good candidate for this challenging era of daily oncologic practice. Also, the combination of docetaxel and ATRA might allow a reduction in docetaxel doses and by this way may diminish docetaxel adverse effects while maintaining the therapeutic effect in patients with HRPC.

Electronic supplementary materialThe online version of this article doi:10.1186-1756-9966-27-37 contains supplementary material, which is available to authorized users.

Yuksel Kucukzeybek, Mustafa K Gul, Ercument Cengiz, Cigdem Erten, Burcak Karaca, Gurbuz Gorumlu, Harika Atmaca, Selim Uzunoglu, Bulent Karabulut, Ulus A Sanli contributed equally to this work.

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Autor: Yuksel Kucukzeybek - Mustafa K Gul - Ercument Cengiz - Cigdem Erten - Burcak Karaca - Gurbuz Gorumlu - Harika Atmaca - Sel

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







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