Repurposing auranofin to treat TP53-mutated or PTEN-deleted refractory B-cell lymphoma

摘要

Dose-response curve for DLBCL treated with auranofin for 72 h. Red = GCB type; Blue = ABC type. Dose-response curve for various MCL cell lines treated with auranofin for 72 h. Averaged auranofin IC calculated from repeated non-linear regression of dose-response curves. Mino, Maver-1, and OCI-Ly8 cell lines were immunoblotted by anti-TP53 antibody after 48-h knockdown of TP53 by siRNA (siTP53) and scrambled siRNA (siScr), and auranofin-treated dose-response growth curves were shown at the presentence of siTP53 or siScr for 72 h. JVM-2 and OCI-Ly3 cell lines were immunoblotted by anti-PTEN antibody after 48-h knockdown of PTEN by siRNA (siPTEN) and siScr, and auranofin-treated dose-response growth curves were shown at the presentence of siPTEN or siScr for 72 h. Immunoblot of Txnrd1 and GPX1 in MCL and DLBCL. Txnrd1 protein level, and GPX1 protein level to the relation with IC of auranofin in DLBCL and MCL cell lines. A Pearson’s correlation test was performed with  k Mino, Maver-1, and . OCI-Ly8 and OCI-Ly10 cell lines were immunoblotted by anti-Txnrd1 antibody after 48-h knockdown of Txnrd1 by siRNA (siTxnrd1) and siScr, and auranofin-treated dose-response growth curves were shown at the presentence of siTP53 or siScr for 72 h. Auranofin-induced apoptosis at 24 h as measured by Annexin-V binding assay. The in vivo effects of auranofin in -mutated DLBCL PDX model. Mice were administered vehicle control or auranofin 50 mg/kg, oral gavage, daily for 21 consecutive days after 3 days of tumor engraftment. Tumor burden was calculated by measuring tumor volume (  = 5; auranofin vs. vehicle,  = 0.000213). Body weight was calculated during drug treatment (auranofin vs. vehicle,  = 0.01556).