Drug interactions between the proteasome inhibitor bortezomib and cytotoxic chemotherapy, tumor necrosis factor (TNF) alpha, and TNF-related apoptosis-inducing ligand in prostate cancer.

Purpose: Proteasome inhibition has been shown to be an effective anticancer therapy in many tumor models, including prostate cancer. We sought to identify drug interactions between the proteasome inhibitor bortezomib and other apoptotic stimuli, including cytotoxic chemotherapy and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In addition, we wanted to gain insight into the role of nuclear factor kappaB inhibition as a mediator of bortezomib cytotoxic effects.

Experimental Design: Prostate cancer cell lines (LNCaP, LAPC4, CL1, and DU145) were treated with bortezomib and apoptotic stimuli (TRAIL, chemotherapy, and tumor necrosis factor alpha), alone or in combination. Apoptosis and cell viability were measured, and median effect/combination index analyses were used to quantitate drug interactions. Nuclear factor kappaB activity at baseline and in response to drug treatment was determined by gel shift and reporter gene assays.

Results: Bortezomib induced cell death of androgen-dependent (LNCaP and LAPC4) and androgen-independent (CL1 and DU145) prostate cancer cell lines, although androgen-dependent cells were more sensitive to proteasome inhibition. Bortezomib synergized with TRAIL and tumor necrosis factor alpha to induce death in both androgen-dependent and androgen-independent cells.

Conclusions: Bortezomib and TRAIL represent a synergistic drug combination that warrants further evaluation in in vivo models of prostate cancer.