Fig. 3.

BCL2 inhibitors deplete MCL1 in DLBCL cells harboring NOXA gene amplification by a caspase-dependent mechanism. (A) DLBCL cells Ri-1 and U-2932 harboring NOXA genetic amplification were incubated with 0.25 μM of S55746 or venetoclax (ABT199) for 72 h. Neither drug had an effect on BCL2 protein levels, but both drugs depleted MCL1 protein. Within the time frame and drug concentrations, BCL2 inhibitors also increased NOXA protein levels in these cell lines. (B) S55746-induced MCL1 depletion was prevented by the pan-caspase inhibitor Z-VAD-fmk. Ri-1 cells were incubated with S55746 (0.05 μM) and increasing concentrations of ZVAD-fmk for 24 h, before protein levels were determined by Western blotting. In the absence of caspase inhibition, S55746 cleaved caspase 3 and PARP and depleted MCL1. These events were reversed by the pan-caspase inhibitor ZVAD-fmk.