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In Vitro Study Comparing the Efficacy of the Water 1296 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 38: 1296-1302, 2016 In vitro study comparing the efficacy of the water-soluble HSP90 inhibitors, 17-AEPGA and 17-DMAG, with that of the non-water-soluble HSP90 inhibitor, 17-AAG, in breast cancer cell lines TARIK GHADBAN1*, ANDRÉ JESSEN1*, MATTHIAS REEH1, JUDITH L. DIBBERN1, SVEN MAHNER2,3, VOLKMAR MUELLER2, ULRICH F. WELLNER4, CENAP GÜNGÖR1, JAKOB R. IZBICKI1 and YOGESH K. VASHIST1,5 1Department of General, Visceral and Thoracic Surgery and 2Gynecology Department and Clinic, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg; 3Department of Gynecology and Obstetrics, University of Munich, 80337 Munich; 4Clinic for Surgery, University Clinic of Schleswig-Holstein, Campus Lübeck, D-23538 Lübeck, Germany; 5Department of Visceral Surgery, Kantonsspital Aarau AG, CH-5001 Aarau, Switzerland Received March 24, 2016; Accepted July 22, 2016 DOI: 10.3892/ijmm.2016.2696 Abstract. Heat shock protein (HSP)90 has emerged as an polymerase (PARP) assay at the concentration of 1 µM of the important target in cancer therapeutics. Diverse HSP90 inhibitors. HSP70 was upregulated, but HSP27 expression was inhibitors are under evaluation. The aim of the present study not affected. Our data indicate that 17-AEPGA and 17-DMAG was to investigate the growth inhibitory effects of the newly are highly active in breast cancer cell lines and may help to developed water-soluble HSP90 inhibitors, 17-[2-(Pyrrolidin- overcome the delivery issues associated with the use of 17-AAG. 1-yl)ethyl]amino-17-demethoxygeldanamycin (17-AEPGA) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin Introduction (17-DMAG), compared to that of the non-water-soluble HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG). Breast cancer (BC) is the most common malignant disease The anti-proliferative effects of the 3 drugs on the human affecting women. Almost every eighth woman will suffer from breast cancer cell lines, MCF-7, SKBR-3 and MDA-MB-231, this disease during her life (1). Multimodal therapy comprising were examined in vitro. In addition, tumor progression factors, surgery, radiotherapy, chemotherapy, endocrine therapy and including human epidermal growth factor receptor 2 (HER2), targeted therapy is the standard approach for the treatment of epidermal growth factor receptor 1 (EGFR1) and insulin-like BC (2,3). Advances in our understanding of the crucial pathways growth factor type 1 receptor (IGF1R), as well as apoptotic and factors involved in the development and progression of BC markers were analysed. We found a time- and dose-dependent have led to the establishment of predictive factors and targeted effect in all the tested cell lines. The effects of 17-AEPGA therapies for BC (4). However, targeted therapies are mostly effec- and 17-DMAG were equal or superior to those of 17-AAG. tive specifically towards a single factor or pathway and acquired The 50% growth inhibition concentration was <2 µM for the resistance during therapy is a phenomenon often observed in the water-soluble compounds following 72 h of exposure. The clinic (5,6). Oncogene switching or the reactivation of signaling significant inhibition of HER2, EGFR1 and IGF1R protein pathways by upstream activators leading to the reactivation of expression was already evident at the concentration of 1 µM. downstream signaling pathways counteract all efforts to prevent Apoptosis was examined by caspase-3 and poly(ADP-ribose) tumor growth and progression in such a setting. Therefore, a simultaneous targeting of multiple effectors and pathways by a single agent represents a promising therapeutic approach. Heat shock protein (HSP)90 is a key modulator of post-translational protein folding and has emerged as a target Correspondence to: Dr Yogesh K. Vashist, Department of General, in anticancer therapy in recent years. HSP90 is ubiquitously Visceral and Thoracic Surgery, University Medical Center Hamburg- expressed, but is highly active only in tumor tissue. HSP90 Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany E-mail: [email protected]; [email protected] belongs to the family of chaperones and ensures the maturation of a wide range of effectors, so-called client proteins (CPs), which *Contributed equally are involved in cell growth, differentiation and survival (7,8). In BC in particular, HSP90 is a very promising therapeutic target, Key words: heat shock protein 90, breast neoplasms, 17-AAG, as human epidermal growth factor receptor 2 (HER2), estrogen 17-AEP-GA, 17-DMAG receptor (ER) and progesterone receptor (PR) are known CPs of HSP90 (9). Furthermore, the phosphatidyl-inositol pathway GHADBAN et al: HSP90 INHIBITION IN BREAST CANCER 1297 that is regulated by AKT (AKR mouse thymoma kinase), a CP woman at Memorial Sloan-Kettering Cancer Center in 1970, of HSP90, has been shown to be involved in the resistance of and it is characterized by HER2 overexpression and the lack BC to chemotherapy (10). In a previous study using a xenograft of ER and PR expression. The MDA-MB-231 BC cell line was model, the inhibition of HSP90 was shown to be associated obtained from a 51-year-old Caucasian woman in 1973, by with the modulation of angiogenesis (11) and HSP90 expression Dr R. Calleau at the University of Texas MD Anderson Cancer has been reported to correlate with a poor outcome in BC (12). Center and has no expression of PR, ER or HER2. The function of HSP90 is dependent upon ATP. The natural ansamycin antibiotic, geldanamycin, binds to the ATP binding Evaluation of cell doubling time and determination of 50% cell site at the N-terminus of HSP90, inhibiting the ATPase activity growth inhibition (GI50). The anti-proliferative activity of of HSP90, which leads to the degradation of the CP (13); all 3 tested HSP90 inhibitors was determined in vitro using therefore, many oncogenic signals can be blocked simul- the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium taneously by the inhibition of HSP90 (14). The well-known bromide colorimetric method, also known as the MTT reduc- semi-synthetic derivate, 17-allylamino-17-demethoxy- tion assay. This assay is based on the ability of viable cells to geldanamycin (17-AAG), has undergone phase II/III clinical reduce MTT-tetrazolium salt into MTT-formazan by the mito- trials (26). However, the lack of solubility in physiological chondrial enzyme succinate-dehydrogenase. fluids makes formulation for clinical delivery a challenge and Before initiating the proliferation assay, the cell doubling limits its clinical use. In an aim to couneract this problem, new time of each tested cell line was evaluated by MTT assay. water-soluble geldanamycin derivates have been developed, Subsequently, the MCF-7, SKBR-3 and MDA-MB-231 cancer such as 17-dimethylaminoethylamino-17-demethoxygel- cells were cultured in 96-well microtiter plates and seeded danamycin (17-DMAG) and 17-[2-(Pyrrolidin-1-yl)ethyl]amino- at pre-determined densities. Ensuring cell confluence rates 17-demethoxygeldanamycin (17-AEPGA) (15-18). of >60%, fresh medium with or without each HSP90 inhibitors In the present study, we compared the growth inhibitory was added at various concentrations for 1, 2 or 3 doubling times. effects of the water-soluble HSP90 inhibitors, 17-DMAG and Subsequently, 12.5 ml of an MTT solution in medium (5 mg/ml 17-AEPGA, to those of 17-AAG (not water soluble) on 3 different MTT; Sigma Chemical Co., St. Louis, MO, USA) was added for human BC cell lines expressing clinically relevant targets 3 h. The medium was removed and the MTT-formazan crystals (MCF-7, SKBR-3 and MDA-MB-231) in vitro. Furthermore, we were solubilised by the addition of DMSO (100 ml/well). The examined the effects of HSP90 inhibition at the molecular level absorbance was determined at 562 nm. The drug concentration focusing on known BC survival and progression factors, such inhibiting 50% (IC50) growth compared to the untreated cells as HER2, epidermal growth factor receptor 1 (EGFR1) and was calculated. insulin-like growth factor type 1 receptor (IGF1R). In addition, other heat shock proteins, such as HSP70 and HSP27, relevant Cell proliferation assay. The MCF-7, SKBR-3 and to HSP90 inhibition (19,20), were analysed. MDA-MB-231 cancer cells were harvested by trypsiniza- tion, counted and 100 µl of cell suspension was filled in each Materials and methods well of 96-well plates at concentrations of 10x10³ cells/well. Ensuring cell confluence rates of >60%, fresh medium with Compounds. For in vitro experiments, 17-DMAG or without 17-AAG, 17-DMAG and 17-AEPGA was added at (cat. no. ant-dgl) and 17-AEPGA (cat. no. ant-egl-1) (both from concentrations from 0.1 to 10 µM for 48 or 72 h. MTT assay InvivoGen, San Diego, CA, USA) were dissolved in water to a was performed as described above. The results were expressed stock concentration of 1 mM and used at final concentrations as a percentage of the control. The absorbance of the control ranging from 0.1 to 10 µM. 17-AAG (cat. no. ant-agl; InvivoGen) (cell culture without any treatment) corresponds to 100% MTT was dissolved in DMSO to a stock concentration of 1 mM and reduction. Six independent experiments were performed for the same final concentrations (0.1‑10 µM) were used. The stock each cell line and the data are presented as the means ± SD. solutions were stored at ‑20˚C. Western blot analysis. To verify the effects of HSP90 inhibition Cell lines. The established human BC cell lines, MCF-7, SKBR-3 at the molecular level, particularly at the protein level, western and MDA-MB-231, were obtained from the American Type blot analyses of all 3 human BC cell lines following treatment Culture Collection (ATCC, Manassas, VA, USA) and cultured with 17-AAG, 17-AEPGA and 17-DMAG were performed. in RPMI-1640 medium (cat.
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