Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma

摘要: HTLV-I associated adult T-cell leukemia (ATL) and HTLV-I-negative peripheral lymphomas are with poor prognosis. Using pharmacological concentrations of the proteasome inhibitor PS-341, we demonstrate inhibition cell proliferation induction apoptosis in fresh ATL cells, transformed malignant T while normal resting or activated lymphocytes were resistant. Combination PS-341 doxorubicin etoposide resulted an additive growth inhibition. In treatment significantly downregulated antiapoptotic protein X-IAP to a lesser extent c-IAP-1 bcl-XL caspase-dependent apoptosis. proteasomal degradation Tax by likely explains relative protection infected cells against these stabilized IκBα, IκBβ, IκBɛ, p21, p27 p53 proteins selectively inhibited Rel-A DNA binding NF-κB complexes. both HTLV-I-positive -negative induced ceramide accumulation that correlated We conclude affects multiple pathways critical for survival supporting potential therapeutic role lymphomas, whether alone combination chemotherapy.