Abstract
Proteasome inhibitors (PIs) have emerged as an attractive novel cancer therapy. However, most solid cancers are seemingly resistant to PIs. The activation of transcription factor Nuclear factor erythroid 2 related factor-1 (NFE2L1) has been characterized as a potential resistance response to protect and restore proteasome activity in cancer cells. In this study, we demonstrated that α-Tocotrienol (T3) and redox-silent analogs of vitamin E (TOS, T3E) enhanced the sensitivity of bortezomib (BTZ), a proteasome inhibitor, in solid cancers through modulation of NFE2L1. In BTZ treatment, all of T3, TOS, and T3E inhibited an increase in the protein levels of NFE2L1, the expression levels of proteasome-related proteins, as well as the recovery of proteasome activity. Moreover, the combination of one of T3, TOS, or T3E and BTZ induced a significant decrease in cell viability in solid cancer cell lines. These findings suggested that the inactivation of NFE2L1 by T3, TOS, and T3E is essential to potentiate the cytotoxic effect of the proteasome inhibitor, BTZ, in solid cancers.