Poloxamer P85 increases anticancer activity of Schiff base against prostate cancer in vitro and in vivo Selami Demirci a , Ayşegül Doğan a , Neşe Başak Türkmen d , Dilek Telci a , Ahmet B. Çağlayan c , Mustafa Ç. Beker c , Ertuğrul Kılıç c , Ferda Özkan b , Bülent Dede e and Fikrettin Şahin a Prostate cancer is the second most common cancer among men and the leading cause of death after lung cancer. Development of hormone-refractory disease is a crucial step for prostate cancer progression for which an effective treatment option is currently unavailable. Therefore, there is a need for new agents that can efficiently target cancer cells, decrease tumor growth, and thereby extend the survival of patients in late-stage castration-resistant prostate cancer. In the current study, a novel heterodinuclear copper(II)Mn(II) Schiff base complex combined with P85 was used to evaluate anticancer activity against prostate cancer in vitro and in vivo. Cell proliferation and cytotoxicity were evaluated by cell viability, gene, and protein expression assays in vitro. Results showed that the heterodinuclear copper(II)Mn(II) complex–P85 combination decreased cell proliferation by upregulating the apoptotic gene expressions and blocking the cell proliferation-related pathways. Tramp-C1-injected C57/B16 mice were used to mimic a prostate cancer model. Treatment combination of Schiff base complex and P85 significantly enhanced the cellular uptake of chemicals (by blocking the drug transporters and increased life time), suppressed tumor growth, and decreased tumor volume steadily over the course of the experiments. Overall, heterodinuclear copper(II)Mn(II) complex–P85 showed remarkable anticancer activity against prostate cancer in in vitro and in vivo. Anti-Cancer Drugs 00:000–000 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Anti-Cancer Drugs 2017, 00:000–000 Keywords: castration-resistant prostate cancer, P85, poloxamer, prostate cancer, Schiff base a Department of Genetics and Bioengineering, Faculty of Engineering, b Department of Pathology, Faculty of Medicine, Yeditepe University, c Department of Physiology, Faculty of Medicine, Istanbul Medipol University, Istanbul, d Department of Pharmaceutical Toxicology, University of Inonu, Malatya and e Department of Chemistry, Faculty of Sciences and Arts, Süleyman Demirel University, Isparta, Turkey Correspondence to Ayşegül Doğan, PhD, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University Kayisdagi, 34755 Istanbul, Turkey Tel: + 90 216 578 0619; fax: + 90 216 578 0829; e-mails: aguldgn@gmail.com, aysegul.dogan@nih.gov Present address: Selami Demirci: National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA. Present address: Ayşegül Doğan: National Cancer Institute, CDBL, NIH, Frederick, Maryland, USA. Received 9 January 2017 Revised form accepted 21 May 2017 Introduction Prostate cancer is the second most frequently diagnosed cancer among men and also the leading cause of death (9% mortality ratio) after lung cancer [1]. Regulation of prostate cancer is a multistep process controlled by androgens at the cellular and molecular levels through androgen and tyrosine kinase receptor mutations, amplifications, or enhancement the sensitivity of recep- tors to growth factors [2]. Development of androgen independency is one of the biggest problems during the treatment of prostate cancer. Androgen-deprivation therapy as a standard treatment can enhance the sensi- tivity of cells to chemotherapy and radiotherapy. Development of castration-resistant prostate cancer (CRPC) is a major challenge for prostate cancer therapy when hormone-deprivation therapy cannot prevent cancer growth [3]. Surgical removal, antiandrogens, chemother- apy, and radiotherapy are the treatment options generally applied for advanced-stage prostate cancer [4,5]. The heterogenic nature of prostate cancer is exemplified by the tumor response variability to chemotherapy underscoring the challenge [6]. Although a combination of chemother- apeutic agents is considered to be an effective treatment strategy for prostate cancer, there is a scarcity of data on the enhanced survival rates or improved quality of life of patients. Besides, patient survival rates are lower compared with the higher toxicity associated with combinatorial treatment [7]. There are several available Food and Drug Administration approved chemother- apeutics such as estramustine, mitoxantrone, docetaxel, and cabazitaxel for the prostate cancer treatment [4]. Docetaxel and cabazitaxel are taxane group che- motherapeutics, and act on the microtubule structure, P-glycoprotein, and multidrug-resistance protein-1 (MRP- 1) [3]. The activity of these chemotherapeutics is impaired because of the amplification of these drug transporters [8]. Although docetaxel is the most promising available chemotherapeutic in the market, acquired resistance is a major problem and response in CRPC is not satisfactory. Therefore, development of new chemotherapeutics, Preclinical report 1 0959-4973 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/CAD.0000000000000528 Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.