Seliciclib treatment results in down-regulation of Mcl-1, associated with inhibition of STAT3 phosphorylation and independent of caspase cleavage, in MM cells sensitive and resistant to conventional therapies. MM1.S cells were incubated with seliciclib (25 μM) for 2, 4, 6, and 8 hours; seliciclib treatment resulted in down-regulation of Mcl-1, associated with time-dependent inhibition of pSTAT3 (A). Pretreatment of MM cells with Z-VAD-FMK followed by seliciclib for 6 hours resulted in down-regulation of Mcl-1 despite blocking caspase activity (B), suggesting that Mcl-1 down-regulation is independent of caspase cleavage. Mcl-1 protein expression was also down-regulated in resistant cell lines (Dox-40 and LR5) by seliciclib treatment for 6 hours (C).