6-O-Carboxypropyl-α-Tocotrienol Enhances the Anticancer Effects of Bortezomib Without Suppressing NRF1 and NRF3 in Colorectal Cancer Cells

Background/Aim: Bortezomib, a proteasome inhibitor, exhibits limited efficacy against colorectal cancer (CRC); therefore, strategies to enhance bortezomib sensitivity in CRC are required. Previous studies have reported that 6-O-carboxypropyl-α-tocotrienol (T3E) enhances bortezomib sensitivity in several cancer cells. In this study, we investigated the anticancer effect of combined treatment with T3E and bortezomib in CRC cells.

Materials and Methods: Cells were treated with T3E and bortezomib in combination, and cell viability, apoptosis, proteasome activity, and endoplasmic reticulum stress induction were evaluated. In addition, we assessed the effects of T3E on the activation of nuclear factor erythroid 2-related factor 1 (NRF1) and nuclear factor erythroid 2-related factor 3 (NRF3), which are involved in bortezomib resistance.

Results: The combined treatment with T3E and bortezomib induced more potent cytotoxicity against CRC cells than either treatment alone. Furthermore, T3E enhanced bortezomib-induced proteasome inhibition and endoplasmic reticulum stress. Notably, the combined treatment with T3E and bortezomib did not induce cytotoxicity in non-cancerous cells. We also observed that T3E did not suppress NRF1 and NRF3, which are resistance factors to bortezomib. Rather, T3E sustained the activation of NRF1 induced by bortezomib.

Conclusion: T3E enhanced the anticancer effects of bortezomib without suppressing NRF1 and NRF3. T3E may be a promising compound for expanding the therapeutic use of bortezomib in CRC.