The PI3K inhibitor GDC-0941 enhances radiosensitization and reduces chemoresistance to temozolomide in GBM cell lines

Neuroscience. 2017 Mar 27;346:298-308. doi: 10.1016/j.neuroscience.2017.01.032. Epub 2017 Jan 29.

Abstract

Glioblastoma multiforme (GBM) is among the most lethal of all human tumors. It is the most frequently occurring malignant primary brain tumor in adults. The current standard of care (SOC) for GBM is initial surgical resection followed by treatment with a combination of temozolomide (TMZ) and ionizing radiation (IR). However, GBM has a dismal prognosis, and survivors have compromised quality of life owing to the adverse effects of radiation. GBM is characterized by overt activity of the phosphoinositide 3-kinase (PI3K) signaling pathway. GDC-0941 is a highly specific PI3K inhibitor with promising anti-tumor activity in human solid tumors. It is being evaluated in Phase II clinical trials for the treatment of breast and non-squamous cell lung cancer. We hypothesized that GDC-0941 may act as an antitumor agent and potentiate the effects of TMZ and IR. In this study, GDC-0941 alone induced cytotoxicity and pro-apoptotic effects. Moreover, combined with the standard GBM therapy (TMZ and IR), it suppressed cell viability, showed enhanced pro-apoptotic effects, augmented autophagy response, and attenuated migratory/invasive capacity in three glioma cell lines. Protein microarray analyses showed that treatment with TMZ+GDC-0941+IR induced higher levels of p53 and glycogen synthase kinase 3-beta (GSK3-β) expression in SHG44GBM cells than those induced by other treatments. This was verified in all cell lines by western blot analysis. Furthermore, the combination of TMZ and GDC-0941 with or without IR reduced the levels of p-AKT and O6-methylguanine DNA methyltransferase (MGMT) in T98G cells. The results of this study suggest that the combination of TMZ, IR, and GDC-0941 is a promising choice for future treatments of GBM.

Keywords: GDC-0941; PI3K inhibitor; TMZ; chemotherapy; glioma; radiotherapy.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis / drug effects
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / pathology
  • Brain Neoplasms / radiotherapy
  • Brain Neoplasms / therapy*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Dacarbazine / therapeutic use
  • Glioblastoma / drug therapy
  • Glioblastoma / pathology
  • Glioblastoma / radiotherapy
  • Glioblastoma / therapy*
  • Humans
  • Indazoles / pharmacology*
  • Indazoles / therapeutic use
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Radiation-Sensitizing Agents / pharmacology*
  • Radiation-Sensitizing Agents / therapeutic use
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Temozolomide

Substances

  • 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
  • Indazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Radiation-Sensitizing Agents
  • Sulfonamides
  • Dacarbazine
  • Phosphatidylinositol 3-Kinase
  • Temozolomide