Overcoming drug resistance in hormone- and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination Ercument Cengiz Æ Burcak Karaca Æ Yuksel Kucukzeybek Æ Gurbuz Gorumlu Æ Mustafa K. Gul Æ Cigdem Erten Æ Harika Atmaca Æ Selim Uzunoglu Æ Bulent Karabulut Æ Ulus A. Sanli Æ Ruchan Uslu Received: 12 November 2008 / Accepted: 3 March 2009 / Published online: 14 March 2009 Ó Springer Science+Business Media B.V. 2009 Abstract Drug resistance is a significant challenge of daily oncology practice. Docetaxel and gossypol both have antitumoral activity in hormone-refractory prostate cancer (HRPC). Our results revealed that docetaxel and gossypol were synergistically cytotoxic and apoptotic in PC-3 cells in a dose- and time-dependent manner. We further inves- tigated the expression profiles of genes involved in drug resistance and metabolism with a Human Cancer Drug Resistance and Metabolism PCR Array Ò (SuperArray). Six of the 84 genes that are known to regulate drug resistance, metabolism, cell cycle, DNA repair and oncogenesis were downregulated C3-fold change by the combination treatment. These results may be important in devising mechanism-based and targeted therapeutic strategies for prostate cancer, especially in devising combination therapy for drug resistant prostate cancers. Keywords Docetaxel Á Gossypol Á PCR array Á Drug resistance Á PC-3 Introduction Although recent progress in the development of chemo- therapeutics have led to success in the treatment of prostate cancer, drug resistance still remains as a significant chal- lenge of daily oncology practice [1–3]. In the past, the multidrug resistance (MDR) phenotype was accepted to be mainly due to the P- glycoprotein overexpression [4]. However, studies in the drug resistant cancer cell lines have identified several alternative different drug resistance mechanisms such as, altered DNA repair, inhibition of apoptosis and reduced intracellular concentration of che- motherapeutic agents [5–8]. It is not clear whether these mechanisms occur sequentially or concurrently in the cancer cell. Docetaxel, a semi-synthetic member of the taxane family, mainly targets the microtubules in the cancer cells. Stabilization of microtubules results in arrest in mitosis and leads to cell death in many type of solid tumors, including hormone-refractory prostate cancer (HRPC) [9, 10]. It has been also reported that docetaxel downregulates some genes that take role in cell prolifer- ation, mitotic spindle formation, transcription factors and, oncogenesis [11]. Although docetaxel chemotherapy has become the first-line standard of care for HRPC based on the results of two large randomized trials, PSA responses rarely exceed 50% and median survival is less than 20 months, thus the use of chemotherapy in this disease remains a subject of active clinical investigation [3–12]. There are also some problems encountered during doce- taxel treatment including serious side effects in most of the patients [13]. Investigators are now focused on how to enhance the cytostatic and cytotoxic effects of docetaxel by combining it with novel anticancer agents for the treatment of prostate cancer. Gossypol is a yellowish compound extracted from cotton plant (Gossypium species) and the tropical tree Thepesia populnea. It was first demonstrated by Tuszyn- ski and Cossu that gossypol has anticancer effects against E. Cengiz Á B. Karaca Á Y. Kucukzeybek Á G. Gorumlu Á M. K. Gul Á C. Erten Á B. Karabulut Á U. A. Sanli Á R. Uslu (&) Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey e-mail: ruchan.uslu@ege.edu.tr H. Atmaca Á S. Uzunoglu Section of Molecular Biology, Department of Biology, Faculty of Science and Arts, Celal Bayar University, Muradiye, Manisa, Turkey 123 Mol Biol Rep (2010) 37:1269–1277 DOI 10.1007/s11033-009-9501-y