Moiken Mehner1, Carolin Kubelt1, Vivian Adamski1, Christina Schmitt2, Michael Synowitz1, Janka Held-Feindt3. 1. Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, Arnold-Heller-Str.3, Building 41, 24105, Kiel, Germany. 2. Department of Anatomy, University of Kiel, 24118, Kiel, Germany. 3. Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, Arnold-Heller-Str.3, Building 41, 24105, Kiel, Germany. Janka.Held-Feindt@uksh.de.
Abstract
PURPOSE: Glioblastoma multiforme (GBM) is a poorly curable disease due to its profound chemoresistance. Despite recent advances in surgery, radiotherapy and chemotherapy, the efficient treatment of GBMs is still a clinical challenge. Beside others, AT101, the R-(-) enantiomer of gossypol, and demethoxycurcumin (DMC), a curcumin-related demethoxy compound derived from Curcuma longa, were considered as possible alternative drugs for GBM therapy. METHODS: Using different human primary GBM cell cultures in a long-term stimulation in vitro model, the cytotoxic and anti-proliferative effects of single and combined treatment with 5 µM AT101 and 5 µM or 10 µM DMC were investigated. Furthermore, western blots on pAkt and pp44/42 as well as JC-1 staining and real-time RT-PCR were performed to understand the influence of the treatment at the molecular and gene level. RESULTS: Due to enhanced anti-proliferative effects, we showed that combined therapy with both drugs was superior to a single treatment with AT101 or DMC. Here, by determination of the combination index, a synergism of the combined drugs was detectable. Phosphorylation and thereby activation of the kinases p44/42 and Akt, which are involved in proliferation and survival processes, were inhibited, the mitochondrial membrane potential of the GBM cells was altered, and genes involved in dormancy-associated processes were regulated by the combined treatment strategy. CONCLUSION: Combined treatment with different drugs might be an option to efficiently overcome chemoresistance of GBM cells in a long-term treatment strategy.
PURPOSE:Glioblastoma multiforme (GBM) is a poorly curable disease due to its profound chemoresistance. Despite recent advances in surgery, radiotherapy and chemotherapy, the efficient treatment of GBMs is still a clinical challenge. Beside others, AT101, the R-(-) enantiomer of gossypol, and demethoxycurcumin (DMC), a curcumin-related demethoxy compound derived from Curcuma longa, were considered as possible alternative drugs for GBM therapy. METHODS: Using different human primary GBM cell cultures in a long-term stimulation in vitro model, the cytotoxic and anti-proliferative effects of single and combined treatment with 5 µM AT101 and 5 µM or 10 µM DMC were investigated. Furthermore, western blots on pAkt and pp44/42 as well as JC-1 staining and real-time RT-PCR were performed to understand the influence of the treatment at the molecular and gene level. RESULTS: Due to enhanced anti-proliferative effects, we showed that combined therapy with both drugs was superior to a single treatment with AT101 or DMC. Here, by determination of the combination index, a synergism of the combined drugs was detectable. Phosphorylation and thereby activation of the kinases p44/42 and Akt, which are involved in proliferation and survival processes, were inhibited, the mitochondrial membrane potential of the GBM cells was altered, and genes involved in dormancy-associated processes were regulated by the combined treatment strategy. CONCLUSION: Combined treatment with different drugs might be an option to efficiently overcome chemoresistance of GBM cells in a long-term treatment strategy.
Authors: M A Jarzabek; V Amberger-Murphy; J J Callanan; C Gao; A M Zagozdzon; L Shiels; J Wang; K L Ligon; B E Rich; P Dicker; W M Gallagher; J H M Prehn; A T Byrne Journal: Br J Cancer Date: 2014-11-06 Impact factor: 7.640
Authors: Dorota K Flak; Vivian Adamski; Grzegorz Nowaczyk; Kosma Szutkowski; Michael Synowitz; Stefan Jurga; Janka Held-Feindt Journal: Int J Nanomedicine Date: 2020-10-05
Authors: Deniz Caylioglu; Rieke Johanna Meyer; Dana Hellmold; Carolin Kubelt; Michael Synowitz; Janka Held-Feindt Journal: Int J Mol Sci Date: 2021-03-30 Impact factor: 5.923