LAUSR

rubicin, epirubicin, vinblastine, etoposide, paclitaxel, and topotecan. RTI‐79's PK characteristics are similar to rifabutin and exhibited no overt toxicity in mice at high doses. RTI‐79 did not exacerbate the known cardiotoxicity associated with doxorubicin as evaluated by body weight, CBCs, and heart function via echocardiograms. RTI‐79 rapidly induced intracellular ROS and increased both mitochondrial membrane potential and fission. The anti‐oxidant quercetin antagonized both RTI‐79‐induced ROS and potentiation of doxorubicin cytotoxicity. RTI‐79 reduced expression of the anti‐oxidant regulator protein, Nrf‐2, potentially through upregulation of SYVN1, an E3 ubiquitin ligase that interacts directly with Nrf‐2. Moreover, RTI‐79 caused upregulation of proteins involved in the unfolded protein response (UPR). Conclusions: RTI‐79 has a broad spectrum of action in both double‐ and triple‐hit DLBCL and synergizes with many different chemotherapeutics to restore drug sensitivity. RTI‐79 works by increasing intracellular ROS, primarily superoxide, through redox cycling. RTI‐79 triggers the UPR that results in increased ubiquitination and loss of Nrf‐2. Thus, RTI‐79 induces oxidative stress by increasing ROS and reducing Nrf‐ 2's ability to respond to ROS. This unique pleiotropic chemosensitizing mechanism provides a novel approach for treating drug resistant cancers.