np-031112 and Brain-Neoplasms

Neuroblastoma (NB) is the most frequently diagnosed extracranial solid tumor among the pediatric population. It is an embryonic tumor with high relapse rates pertaining to the presence of dormant slowly dividing cancer stem cells (CSC) within the tumor bulk that are responsible for therapy resistance. Therefore, there is a dire need to develop new therapeutic approaches that specifically target NB CSCs. Glycogen synthase kinase (GSK)-3β is a serine/threonine kinase that represents a common signaling node at the intersection of many pathways implicated in NB CSCs. GSK-3β sustains the survival and maintenance of CSCs and renders them insensitive to chemotherapeutic agents and radiation.. In our study, we aimed at evaluating the potential anti-tumor effect of Tideglusib (TDG), an irreversible GSK-3β inhibitor drug, on three human NB cell lines, SK-N-SH, SH-SY5Y, and IMR-32.. Our results showed that TDG significantly reduced cell proliferation, viability, and migration of the NB cells, in a dose- and time-dependent manner, and also significantly hindered the neurospheres formation eradicating the self-renewal ability of highly resistant CSCs. Besides, TDG potently reduced CD133 cancer stem cell marker expression in both SH-SY5Y cells and G1 spheres. Lastly, TDG inhibited NB tumor growth and progression in vivo.. Collectively, we concluded that TDG could serve as an effective treatment capable of targeting the NB CSCs and hence overcoming therapy resistance. Yet, future studies are warranted to further investigate its potential role in NB and decipher the subcellular and molecular mechanisms underlying this role.

Topics: AC133 Antigen; Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Enzyme Inhibitors; Glycogen Synthase Kinase 3 beta; Humans; Mice; Neoplastic Stem Cells; Neuroblastoma; Thiadiazoles; Wound Healing; Xenograft Model Antitumor Assays

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.. 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.. 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.. 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.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Chemoradiotherapy, Adjuvant; DNA Damage; Dose-Response Relationship, Drug; Glioblastoma; Glycogen Synthase Kinase 3 beta; Humans; Neoplastic Stem Cells; Thiadiazoles; Tumor Stem Cell Assay

Topics: Adult; Aged; Aged, 80 and over; Brain; Brain Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Female; Glioblastoma; Glycogen Synthase Kinase 3 beta; Hexanones; Humans; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Male; Middle Aged; Phosphorylation; Primary Cell Culture; Prognosis; Protein Stability; Pyridines; Pyrimidines; RNA, Small Interfering; Signal Transduction; Thiadiazoles; Xenograft Model Antitumor Assays