Jolie Bou-Gharios1,2, Sahar Assi1, Hisham F Bahmad1,3, Youssef Fares4, Wassim Abou-Kheir5, Hussein Kharroubi1, Tarek Araji1, Reda M Chalhoub1,6, Farah Ballout1, Hayat Harati2. 1. Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, DTS Bldg, Room 116-B, Riad el Solh, PO Box 110236/41, Beirut, 1107-2020, Lebanon. 2. Chair of Neurosurgery Department, Faculty of Medicine, Neuroscience Research Center, Lebanese University, Beirut, Lebanon. 3. Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA. 4. Chair of Neurosurgery Department, Faculty of Medicine, Neuroscience Research Center, Lebanese University, Beirut, Lebanon. yfares@ul.edu.lb. 5. Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, DTS Bldg, Room 116-B, Riad el Solh, PO Box 110236/41, Beirut, 1107-2020, Lebanon. wa12@aub.edu.lb. 6. Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Abstract
BACKGROUND: Glioblastoma multiforme (GBM), a stage IV astrocytoma, is the most common brain malignancy among adults. Conventional treatments of surgical resection followed by radio and/or chemotherapy fail to completely eradicate the tumor. Resistance to the currently available therapies is mainly attributed to a subpopulation of cancer stem cells (CSCs) present within the tumor bulk that self-renew leading to tumor relapse with time. Therefore, identification of characteristic markers specific to these cells is crucial for the development of targeted therapies. Glycogen synthase kinase 3 (GSK-3), a serine-threonine kinase, is deregulated in a wide range of diseases, including cancer. In GBM, GSK-3β is overexpressed and its suppression in vitro has been shown to induce apoptosis of cancer cells. METHODS: In our study, we assessed the effect of GSK-3β inhibition with Tideglusib (TDG), an irreversible non-ATP competitive inhibitor, using two human GBM cell lines, U-251 MG and U-118 MG. In addition, we combined TDG with radiotherapy to assess whether this inhibition enhances the effect of standard treatment. RESULTS: Our results showed that TDG significantly reduced cell proliferation, cell viability, and migration of both GBM cell lines in a dose- and time-dependent manner in vitro. Treatment with TDG alone and in combination with radiation significantly decreased the colony formation of U-251 MG cells and the sphere formation of both cell lines, by targeting and reducing their glioblastoma cancer stem-like cells (GSCs) population. Finally, cells treated with TDG showed an increased level of unrepaired radio-induced DNA damage and, thus, became sensitized toward radiation. CONCLUSIONS: In conclusion, TDG has proven its effectiveness in targeting the cancerous properties of GBM in vitro and may, hence, serve as a potential adjuvant radio-therapeutic agent to better target this deadly tumor.
BACKGROUND:Glioblastoma multiforme (GBM), a stage IV astrocytoma, is the most common brain malignancy among adults. Conventional treatments of surgical resection followed by radio and/or chemotherapy fail to completely eradicate the tumor. Resistance to the currently available therapies is mainly attributed to a subpopulation of cancer stem cells (CSCs) present within the tumor bulk that self-renew leading to tumor relapse with time. Therefore, identification of characteristic markers specific to these cells is crucial for the development of targeted therapies. Glycogen synthase kinase 3 (GSK-3), a serine-threonine kinase, is deregulated in a wide range of diseases, including cancer. In GBM, GSK-3β is overexpressed and its suppression in vitro has been shown to induce apoptosis of cancer cells. METHODS: In our study, we assessed the effect of GSK-3β inhibition with Tideglusib (TDG), an irreversible non-ATP competitive inhibitor, using two human GBM cell lines, U-251 MG and U-118 MG. In addition, we combined TDG with radiotherapy to assess whether this inhibition enhances the effect of standard treatment. RESULTS: Our results showed that TDG significantly reduced cell proliferation, cell viability, and migration of both GBM cell lines in a dose- and time-dependent manner in vitro. Treatment with TDG alone and in combination with radiation significantly decreased the colony formation of U-251 MG cells and the sphere formation of both cell lines, by targeting and reducing their glioblastoma cancer stem-like cells (GSCs) population. Finally, cells treated with TDG showed an increased level of unrepaired radio-induced DNA damage and, thus, became sensitized toward radiation. CONCLUSIONS: In conclusion, TDG has proven its effectiveness in targeting the cancerous properties of GBM in vitro and may, hence, serve as a potential adjuvant radio-therapeutic agent to better target this deadly tumor.
Authors: Roger Stupp; Pierre-Yves Dietrich; Sandrine Ostermann Kraljevic; Alessia Pica; Ivan Maillard; Phillipe Maeder; Reto Meuli; Robert Janzer; Gianpaolo Pizzolato; Raymond Miralbell; François Porchet; Luca Regli; Nicolas de Tribolet; René O Mirimanoff; Serge Leyvraz Journal: J Clin Oncol Date: 2002-03-01 Impact factor: 44.544
Authors: Roger Stupp; Warren P Mason; Martin J van den Bent; Michael Weller; Barbara Fisher; Martin J B Taphoorn; Karl Belanger; Alba A Brandes; Christine Marosi; Ulrich Bogdahn; Jürgen Curschmann; Robert C Janzer; Samuel K Ludwin; Thierry Gorlia; Anouk Allgeier; Denis Lacombe; J Gregory Cairncross; Elizabeth Eisenhauer; René O Mirimanoff Journal: N Engl J Med Date: 2005-03-10 Impact factor: 91.245
Authors: Roger Stupp; Monika E Hegi; Warren P Mason; Martin J van den Bent; Martin J B Taphoorn; Robert C Janzer; Samuel K Ludwin; Anouk Allgeier; Barbara Fisher; Karl Belanger; Peter Hau; Alba A Brandes; Johanna Gijtenbeek; Christine Marosi; Charles J Vecht; Karima Mokhtari; Pieter Wesseling; Salvador Villa; Elizabeth Eisenhauer; Thierry Gorlia; Michael Weller; Denis Lacombe; J Gregory Cairncross; René-Olivier Mirimanoff Journal: Lancet Oncol Date: 2009-03-09 Impact factor: 41.316
Authors: Zahraa F Audi; Zahraa Saker; Mahdi Rizk; Hisham F Bahmad; Sanaa M Nabha; Hayat Harati; Youssef Fares Journal: Curr Treat Options Oncol Date: 2021-07-30
Authors: Hisham F Bahmad; Darine Daher; Abed A Aljamal; Mohamad K Elajami; Kei Shing Oh; Juan Carlos Alvarez Moreno; Ruben Delgado; Richard Suarez; Ana Zaldivar; Roshanak Azimi; Amilcar Castellano; Robert Sackstein; Robert J Poppiti Journal: J Histochem Cytochem Date: 2021-06-24 Impact factor: 2.479