PS-341 or a combination of arsenic trioxide and interferon-alpha 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-alpha (IFN-alpha) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-kappaB (NF-kappaB) activation. PEL cells also display an activated NF-kappaB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-alpha combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-alpha 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-alpha treatment abrogated NF-kappaB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-X(L). Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-alpha in PEL patients.
Abou-Merhi
R
R
Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
Khoriaty
R
R
Arnoult
D
D
El Hajj
H
H
Dbouk
H
H
Munier
S
S
El-Sabban
M E
ME
Hermine
O
O
Gessain
A
A
de Thé
H
H
Mahieux
R
R
Bazarbachi
A
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D008223:Lymphoma / Q000201:enzymology / Q000473:pathology* / Q000821:virology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010087:Oxides / Q000008:administration & dosage; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism
D001152:Arsenicals; D001897:Boronic Acids; D016898:Interferon-alpha; D016328:NF-kappa B; D010087:Oxides; D011480:Protease Inhibitors; D011719:Pyrazines; D051020:bcl-X Protein; D000069286:Bortezomib; D020169:Caspases; D000077237:Arsenic Trioxide