Syrbactins belong to a new class of
proteasome inhibitors which include syringolins and glidobactins. These small molecules are structurally distinct from other, well-established
proteasome inhibitors, and bind the eukaryotic
20S proteasome by a novel mechanism. In this study, we examined the effects of
syringolin A (SylA) and
glidobactin A (GlbA) as well as two synthetic SylA-analogs (SylA-PEG and SylA-LIP) in human
neuroblastoma (SK-N-SH), human
multiple myeloma (MM1.S, MM1.RL, and U266), and human
ovarian cancer (SKOV-3) cells. While all four syrbactins inhibited cell proliferation in a dose-dependent manner, GlbA was most potent in both
dexamethasone-sensitive MM1.S cells (IC(50): 0.004microM) and
dexamethasone-resistant MM1.RL cells (IC(50): 0.005microM). Syrbactins also inhibited the
chymotrypsin-like
proteasome activity in a dose-dependent fashion, and GlbA was most effective in SK-N-SH cells (IC(50): 0.015microM). The GlbA-promoted inhibition of proteasomal activity in SK-N-SH cells resulted in the accumulation of
ubiquitinated proteins and
tumor suppressor protein p53 and led to apoptotic cell death in a time-dependent manner. GlbA treatment also promoted the activation of Akt/PKB via phosphorylation at residue Ser(473) and induced autophagy as judged by the presence of the lipidated form of
microtubule-associated protein 1 light chain 3 (LC3) and autophagosomes. Collectively, our data suggest that syrbactins belong to a new and effective
proteasome inhibitor class which promotes cell death.
Proteasome inhibition is a promising strategy for targeted anticancer
therapy and syrbactins are a new class of inhibitors which provide a structural platform for the development of novel,
proteasome inhibitor-based
drug therapeutics.