2. Academic Validation
  3. Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination

Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination

  • J Exp Clin Cancer Res. 2017 Sep 5;36(1):118. doi: 10.1186/s13046-017-0588-z.
Xin Zhang 1,  Ran Xu 1,  Chao Zhang 1,  Yangyang Xu 1,  Mingzhi Han 1,  Bin Huang 1,  Anjing Chen 1,  Chen Qiu 2,  Frits Thorsen 3 4,  Lars Prestegarden 3 5,  Rolf Bjerkvig 3 6,  Jian Wang 7 8,  Xingang Li 9
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, 250012, People's Republic of China.
  • 2 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China.
  • 3 Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, 5009, Bergen, Norway.
  • 4 The Molecular Imaging Center, Department of Biomedicine, University of Bergen, 5009, Bergen, Norway.
  • 5 Department of Dermatology, Haukeland University Hospital, 5009, Bergen, Norway.
  • 6 Department of Oncology, Luxembourg Institute of Health, L-1526, Strassen, Luxembourg.
  • 7 Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, 250012, People's Republic of China. jian.wang@uib.no.
  • 8 Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, 5009, Bergen, Norway. jian.wang@uib.no.
  • 9 Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, 250012, People's Republic of China. lixg@sdu.edu.cn.
PMID: 28870216 DOI: 10.1186/s13046-017-0588-z
Abstract

Background: Resistance to Adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Autophagy inhibitors have been shown to enhance the efficacy of radiotherapy for certain solid tumors. However, current inhibitors do not penetrate the blood-brain-barrier (BBB). Here, we assessed the radiosensitivity effects of the antipsychotic drug trifluoperazine (TFP) on GBM in vitro and in vivo.

Methods: U251 and U87 GBM cell lines as well as GBM cells from a primary human biopsy (P3), were used in vitro and in vivo to evaluate the efficacy of TFP treatment. Viability and cytotoxicity was evaluated by CCK-8 and clonogenic formation assays. Molecular studies using immunohistochemistry, western blots, immunofluorescence and qPCR were used to gain mechanistic insight into the biological activity of TFP. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.

Results: IC50 values of U251, U87 and P3 cells treated with TFP were 16, 15 and 15.5 μM, respectively. TFP increased the expression of LC3B-II and p62, indicating a potential disruption of Autophagy flux. These results were further substantiated by a decreased Lysotracker Red uptake, indicating impaired acidification of the lysosomes. We show that TFP and radiation had an additive effect when combined. This effect was in part due to impaired TFP-induced homologous recombination. Mechanistically we show that down-regulation of Cathepsin L might explain the radiosensitivity effect of TFP. Finally, combining TFP and radiation resulted in a significant antitumor effect in orthotopic GBM xenograft models.

Conclusions: This study provides a strong rationale for further clinical studies exploring the combination therapy of TFP and radiation to treat GBM patients.

Keywords

Autophagy inhibitor; Glioblastoma; Homologous recombination; Radiosensitivity; Trifluoperazine.

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