Figure 2.

Schematic representation of MM cells adaptation to elevated intracellular ROS and ROS-mediated PIs resistance. In MM cells, activation of keys oncoproteins (RAS, STAT3, BCL2, MYC) and inactivation of TP53 result in an increase of intracellular ROS. To avoid entering apoptosis, cells adapt their antioxidant capacities and enhance the transcriptional activity of factors targeting GSH- and TXN-dependent enzymes and detoxifying systems. The decrease of GSH and the inhibition of antioxidant enzymes (TXN, TXNRD1) by gold compounds (auranofin) or L-buthionine sulfoximine (BSO), an irreversible inhibitor of the glutamate-cysteine ligase (GCL or γ-glutamylcysteine synthetase), one enzyme of GSH synthesis, as well as the inhibition of mitochondrial respiration complex I with diphenyleneiodonium (DPI), trigger MM cells apoptosis (see chapter 4). Due to genetic and epigenetic changes occurring during PI-treatment, drug resistance rises. In PI-resistant cells, the targeting of antioxidant enzymes (TXN and TXNRD1 inhibitors), or the pool of GSH (BSO and APR-246) is still efficient and restores drug sensitivity. The association of auranofin and BTZ exacerbates the level of ROS and is more efficient for inducing MM cell death.