Bexarotene inhibits cell proliferation by inducing oxidative stress, DNA damage and apoptosis via PPAR gamma/ NF-kappa B signaling pathway in C6 glioma cells

Hacioglu C., Kar F., Kaçar S., Şahintürk V., Kanbak G.

MEDICAL ONCOLOGY, vol.38, no.3, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 38 Issue: 3
  • Publication Date: 2021
  • Doi Number: 10.1007/s12032-021-01476-z
  • Journal Name: MEDICAL ONCOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CINAHL, EMBASE, MEDLINE
  • Keywords: Bexarotene, RXR, Glioma, Apoptosis, Oxidative stress, 8-hydroxydeoxyguanosine, Ppar&#947, NF-&#954, b
  • Kütahya Health Sciences University Affiliated: Yes


Gliomas are one of the most aggressive brain tumors with a poor prognosis in the central nervous system. Bexarotene is a third-generation retinoid X receptor agonist that is promising in the treatment of both cancer and neurodegenerative diseases. In this study, we aimed to investigate the cytotoxic and anti-proliferative effects of bexarotene in C6 glioma cells through the PPAR gamma/NF-kappa B pathway. In the study, first cytotoxic bexarotene concentrations for C6 cells were detected, and then apoptosis profile, reactive oxygen species (ROS), total antioxidant (TAS), 8-hydroxy-2 '-deoxyguanosine (8-OHdG) and nuclear factor-kappa B (NF-kappa B) levels in the cells were determined. In addition, peroxisome proliferator-activated receptor gamma (PPAR gamma) mRNA expression analysis was carried out. As a result, we detected concentration- and time-dependent antiproliferative effects of bexarotene on C6 cells. We found that bexarotene treatment decreased NF-kappa B and TAS levels and increased PPAR gamma and 8-OHdG levels in C6 cells. Bexarotene enhanced PPAR gamma expression in a dose-dependent manner when compared to the control group (P < 0.01). Furthermore, we determined that bexarotene-induced apoptotic C6 cells enhanced through Annexin V-FITC/PI staining and caspase-3/-7 activation analyses since phosphatidylserine level on the outer surface of the cell membrane and caspase-3/-7 activities were increased in the cells treated with bexarotene. In conclusion, bexarotene treatment in C6 glioma cells could modulate apoptosis profile, DNA damage, ROS production, and reduction of TAS levels through inhibition of NF-kappa B by enhancing PPAR gamma expression.