RESEARCH ARTICLE Novel combination of docetaxel and thymoquinone induces synergistic cytotoxicity and apoptosis in DU-145 human prostate cancer cells by modulating PI3K–AKT pathway A. Dirican • H. Atmaca • E. Bozkurt • C. Erten • B. Karaca • R. Uslu Received: 4 June 2014 / Accepted: 9 July 2014 Ó Federacio ´n de Sociedades Espan ˜olas de Oncologı ´a (FESEO) 2014 Abstract Background The treatment of castrate-resistant prostate cancer (CRPC) still remains as an important challenge of daily oncology practice. Docetaxel significantly prolongs overall survival in men with CRPC. Thymoquinone (TQ), one of the flavonoid compounds isolated from Nigealla sativa, has been shown to possess cytotoxic activity against a variety of cancer cell lines. Materials and Methods The aim of the study was to investigate the possible synergistic cytotoxic/apoptotic effects of a novel combination, docetaxel and TQ in DU- 145 hormone- and drug-refractory prostate cancer cells and their effects on PI3K and ERK signaling pathways. Results We observed that the combination of docetaxel and TQ resulted in a significant synergistic cytotoxicy and apoptosis as compared to any single agent alone, in a dose- dependent manner. It was found that viability of the combi- nation treated cells was not significantly changed in the pre- sence of LY294002 as compared to inhibitor treated cells. However, in the presence of FR180204, viability of combi- nation treated cells was significantly decreased as compared to inhibitor treated cells. In conclusion, cytotoxic effect of the docetaxel and TQ combination is correlated with the block of the PI3K/Akt signaling pathway in DU-145 cells. Conclusion Therefore, this combination strategy may be an alternative approach for the challenging era of daily oncologic practice. Also, the combination of docetaxel and TQ might allow a reduction in docetaxel doses and diminish adverse effects of docetaxel while maintaining the therapeutic effect in patients with CRPC. Keywords Thymoquinone Á Docetaxel Á Prostate cancer Á Combination treatment Á PI3K/Akt signaling pathways Introduction Prostate cancer is the most common cancer and the second leading cause of death in men in the United States [1]. The clinical behavior of prostate cancer ranges from a micro- scopic, well-differentiated tumor to an aggressive, invasive cancer that finally results in metastases. Androgen depri- vation therapy (ADT) is the standard initial approach for patients with metastatic prostate cancer. Patients being managed with ADT who have evidence of disease pro- gression (increasing serum PSA, new clinical metastases, progression of existing metastases) are considered to have castrate-resistant prostate cancer (CRPC) [2, 3]. Docetaxel is the only chemotherapeutic agent that significantly pro- long overall survival in clinical trials in men with CRPC [4, 5]. Because options for patients with CRPC are limited A. Dirican (&) Á C. Erten Department of Medical Oncology, Izmir Katip Celebi University Ataturk Training and Research Hospital, 35360 Izmir, Turkey e-mail: ahmetdirican@yahoo.com C. Erten e-mail: cigdemerten@mynet.com H. Atmaca Á E. Bozkurt Section of Molecular Biology, Department of Biology, Faculty of Science and Arts, Celal Bayar University, Manisa, Turkey e-mail: harikatmaca1@gmail.com E. Bozkurt e-mail: emrbzkrt@gmail.com B. Karaca Á R. Uslu Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Izmir, Turkey e-mail: burcakkaraca@ege.edu.tr R. Uslu e-mail: ruchanuslu@ege.edu.tr 123 Clin Transl Oncol DOI 10.1007/s12094-014-1206-6