Antitumor activities of nutlin-3a and genotoxic drugs in MM cells. (A) Western analysis for p53, MDM2, and p21^WAF1 in p53 wild-type MM cells after overnight exposure to either 10 μM nutlin-3a (A), nutlin-3b (B), etoposide (E), or melphalan (M). Etoposide and melphalan activated p53 signaling in NCI-H929, but did so less robustly than the MDM2 inhibitor. A modest increase of p53 levels was seen in MM.1s treated with either genotoxic drug. (B) Dose-response curves revealed EC₅₀ values of 0.32 μM (etoposide) and 3.5 μM (nutlin-3a and melphalan) for NCI-H929 and 0.2 μM (etoposide), 2.5 μM (melphalan), and 5.2 μM (nutlin-3a) for MM.1s, respectively. (C) Effects of either nutlin-3a ((), etoposide (▨), or melphalan (▦), 10 μM, on the 5-day survival of primary myeloma tumor cells in coculture with BMSCs relative to DMSO controls (= 100%). The apoptotic activity of nutlin-3a was similar to melphalan, whereas etoposide had little effect on primary tumor cells.