Caspase inhibition does not inhibit bortezomib-induced death of resistant cells and promotes phenotypic changes reminiscent of autophagy in bortezomib-treated cells. (A) Chemical inhibition of caspase activation inhibited bortezomib-induced cell death of sensitive but not resistant cells. After 72-hour incubations with bortezomib (25nM) alone or combined with the pan-caspase inhibitors zVAD-fmk (50μM) or Q-VD-OPh (5μM), sensitive (Raji, RL) and resistant (Raji 2R, Raji 4RH, RL 4RH) cells were assayed for cell death by propidium iodide uptake. Data shown are averages of at least 3 independent experiments ± SD. Asterisks (*) indicate significant (P < .05) inhibition of bortezomib-induced cell death. Double asterisks (**) indicate significant (P < .05) enhancement of bortezomib-induced cell death. (B) Western blot analysis of whole cell lysates from resistant cells (Raji 2R shown here) treated for 48 hours with bortezomib (25nM) with or without zVAD-fmk (50μM) or Q-VD-OPh (5μM) revealed that addition of pan-caspase inhibitors were sufficient to inhibit bortezomib-induced apoptosis, as demonstrated by inhibition of PARP cleavage.