The triterpenoid CDDO induces apoptosis in refractory CLL B cells

摘要: Chronic lymphocytic leukemia (CLL) cells develop chemo-resistance over time. Most anticancer agents function through induction of apoptosis, and therefore resistance against these is likely to be caused by selection for CLL with defects in the particular apoptosis pathway that triggered drugs. Anticancer alternative apoptotic pathways might useful treating chemo-resistant CLL. Triterpenoids represent a class naturally occurring synthetic compounds demonstrated antitumor activity. We examined effects CDDO (triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) on B vitro. induced dose-dependent manner all (n = 30) samples tested, including previously untreated specimens. rapid proteolytic processing caspase-8, but not caspase-9, cells, suggesting activation mitochondria-independent pathway. CDDO-induced was blocked cytokine response modifier A (CrmA), suppressor X-linked inhibitor protein-baculovirus IAP repeat-3 (XIAP-BIR3), fragment XIAP, which selectively inhibits caspase-9. Examination expression several apoptosis-relevant genes significant reductions levels caspase-8 homolog Fas-ligand interleukin-1-converting enzyme (FLICE)-inhibitory protein (c-FLIP), an endogenous antagonist caspase-8. However, FLIP achieved antisense oligonucleotides were insufficient triggering indicating has other targets besides FLIP. These data suggest triterpenoid should further explored as possible therapeutic agent treatment