δ-Tocotrienol sensitizes and re-sensitizes ovarian cancer cells to cisplatin via induction of G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis

Objectives Among gynaecologic malignancies, ovarian cancer (OC) represents the leading cause of death for women worldwide. Current OC treatment involves cytoreductive surgery followed by platinum-based chemotherapy, which is associated with severe side effects and development of drug resistance. Therefore, new therapeutic strategies are urgently needed. Herein, we evaluated the anti-tumour effects of Vitamin E-derived delta-tocotrienol (delta-TT) in two human OC cell lines, IGROV-1 and SKOV-3 cells. Materials and Methods MTT and Trypan blue exclusion assays were used to assess delta-TT cytotoxicity, alone or in combination with other molecules. delta-TT effects on cell cycle, apoptosis, ROS generation and MAPK phosphorylation were investigated by flow cytometry, Western blot and immunofluorescence analyses. The synergism between delta-TT and chemotherapy was evaluated by isobologram analysis. Results We demonstrated that delta-TT could induce cell cycle block at G1-S phase and mitochondrial apoptosis in OC cell lines. In particular, we found that the proapoptotic activity of delta-TT correlated with mitochondrial ROS production and subsequent JNK and p38 activation. Finally, we observed that the compound was able to synergize with cisplatin, not only enhancing its cytotoxicity in IGROV-1 and SKOV-3 cells but also re-sensitizing IGROV-1/Pt1 cell line to its anti-tumour effects. Conclusions delta-TT triggers G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis in OC cells and sensitizes them to platinum treatment, thus representing an interesting option for novel chemopreventive/therapeutic strategies for OC.

Automated summary

The study found that Vitamin E-derived delta-tocotrienol can induce G1 phase cell cycle arrest and mitochondrial apoptosis in ovarian cancer cells. Additionally, the proapoptotic activity of delta-TT was found to be correlated with mitochondrial ROS production and subsequent activation of JNK and p38. Furthermore, it was observed that delta-TT can synergize with cisplatin, enhancing its cytotoxicity and re-sensitizing ovarian cancer cells to its anti-tumor effects.