PS-341 or a combination of arsenic trioxide and interferon-α inhibit growth and induce caspase-dependent apoptosis in KSHV/ HHV-8-infected primary effusion lymphoma cells

Kaposi's sarcoma (KS)-associated herpes virus (KSHV) is the causative agent of primary effusion lymphoma and of KS. Primary effusion lymphoma (PEL) is an aggressive proliferation of B cells. Conventional chemotherapy has limited benefits in PEL patients, and the prognosis is very poor. We previously reported that treatment of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma cells either with arsenic trioxide (As) combined to interferon-α (IFN-α) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-κB (NF-κB) activation. PEL cells also display an activated NF-κB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-α combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-α treated cells. This was associated with the dissipation of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and was reversed by the z-VAD caspase inhibitor. PS-341 and As/IFN-α treatment abrogated NF-κB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-XL. Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-α in PEL patients.