Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells.

摘要: Purpose: Bcl-2 overexpression is frequently detected in lymphoid malignancies, being associated with poor prognosis and reduced response to therapy. Here, we evaluated whether affects the cytotoxic activity of proteasome inhibitors taken alone or association conventional anticancer drugs tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Experimental Design: Jurkat cells engineered overexpress were treated (MG132, epoxomicin, bortezomib), (etoposide doxorubicin), TRAIL, combinations these compounds. Cell death loss mitochondrial transmembrane potential by flow cytometry. Cytosolic relocalization cytochrome c SMAC/Diablo, caspase cleavage, Mcl-1 levels determined immunoblotting. Nuclear factor-κB inhibition was done retroviral transduction a dominant-negative mutant IκBα. Results: results significant apoptosis inhibitors, antiblastics, TRAIL. Addition TRAIL synergistic effect Bcl-2-overexpressing cells, whereas this result not reproduced combination antiblastic drugs. Importantly, plus induce dysfunction irrespective up-regulated Bcl-2. cleavage fragment putative proapoptotic elimination antiapoptotic may both play role inhibitors-TRAIL cooperation. Conversely, nuclear per se insufficient explain observed synergy. Conclusions: Combined overcome apoptotic threshold raised prove useful treatment chemoresistant malignancies