Multiple myeloma (MM) displays an NFκB activity-related gene expression 
signature and about 20% of primary MM samples harbor genetic alterations 
conducive to intrinsic NFκB signaling activation. The relevance of blocking the 
classical versus the alternative NFκB signaling pathway and the molecular 
execution mechanisms involved, however, are still poorly understood. Here, we 
comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 
inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), 
and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their 
anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the 
classical NFκB pathway, the other two compounds inhibited classical and 
alternative NFκB signaling without significant discrimination. Noteworthy, 
whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to 
moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic 
to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid 
cell swelling and its initial effects were blocked by necrostatin-1 or the ROS 
scavenger BHA, but a lasting protective effect was not achieved even with 
additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB 
pathway downstream of IKK1 at the level of p100 processing, the quite discordant 
effects between MLN4924 and BAY 11-7082 must thus be due to blockade of 
IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an 
off-target effect of BAY 11-7082. In accordance with the latter, we further 
observed that concomitant knockdown of IKK1 and IKK2 did not have any major 
short-term adverse effect on the viability of MM cells.