Figure 8. Cooperative effects of GV and TS on the TR2/TRX2/PRX3 antioxidant network.

Superoxide from the electron transport and chain and other sources is converted by MnSOD to H₂O₂, which is then metabolized by PRX3 to water. Disruption of PRX3 activity by covalent adduction of cysteine residues by TS increases mitochondrial oxidant levels, which repress FOXM1 expression through unknown mechanisms. Inhibition of TRX2 expression by GV potentiates the activity of TS, increasing its cytotoxicity. Combinatorial approaches to inactivating the TR2/TRX2/PRX3 antioxidant network provide an approach for disabling an important adaptive response in MM, and may enhance the sensitivity of MM to conventional chemotherapeutic drugs.