title: 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.
abstract: Heat shock protein (HSP)90 has emerged as an important target in cancer therapeutics. Diverse HSP90 inhibitors are under evaluation. The aim of the present study was to investigate the growth inhibitory effects of the newly developed water-soluble HSP90 inhibitors, 17-[2-(Pyrrolidin-1-yl)ethyl]amino-17-demethoxygeldanamycin (17-AEPGA) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), compared to that of the non-water-soluble HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG). The anti-proliferative effects of the 3 drugs on the human breast cancer cell lines, MCF-7, SKBR-3 and MDA-MB-231, were examined in vitro. In addition, tumor progression factors, including human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 1 (EGFR1) and insulin-like growth factor type 1 receptor (IGF1R), as well as apoptotic markers were analysed. We found a time- and dose-dependent effect in all the tested cell lines. The effects of 17-AEPGA and 17-DMAG were equal or superior to those of 17-AAG. The 50% growth inhibition concentration was <2 µM for the water-soluble compounds following 72 h of exposure. The significant inhibition of HER2, EGFR1 and IGF1R protein expression was already evident at the concentration of 1 µM. Apoptosis was examined by caspase-3 and poly(ADP-ribose) polymerase (PARP) assay at the concentration of 1 µM of the inhibitors. HSP70 was upregulated, but HSP27 expression was not affected. Our data indicate that 17-AEPGA and 17-DMAG are highly active in breast cancer cell lines and may help to overcome the delivery issues associated with the use of 17-AAG.
authors: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Tarik
authors: T
authors: Ghadban
authors: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: André
authors: A
authors: Jessen
authors: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Matthias
authors: M
authors: Reeh
authors: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Judith L
authors: JL
authors: Dibbern
authors: Gynecology Department and Clinic, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Sven
authors: S
authors: Mahner
authors: Gynecology Department and Clinic, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Volkmar
authors: V
authors: Mueller
authors: Clinic for Surgery, University Clinic of Schleswig-Holstein, Campus Lübeck, D-23538 Lübeck, Germany.
authors: Ulrich F
authors: UF
authors: Wellner
authors: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Cenap
authors: C
authors: Güngör
authors: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Jakob R
authors: JR
authors: Izbicki
authors: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Yogesh K
authors: YK
authors: Vashist
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: C548185:17-(2-(pyrrolidin-1-yl)ethyl)-amino-17-demethoxygeldanamycin; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D014867:Water; C112765:tanespimycin