Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants.
Recent studies have shown that the transcription factor nuclear factor kappaB (NF-kappaB) regulates critical survival pathways in a variety of cancers, including human T-cell leukemia/lymphotrophic virus 1 (HTLV-1)-transformed CD4 T cells. The activation of NF-kappaB is controlled by proteasome-mediated degradation of the inhibitor of nuclear factor kappaBalpha (IkappaBalpha). We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome in HTLV-1 Tax transgenic tumors in vitro and in vivo. In Tax transgenic mice, PS-341 administered thrice weekly inhibited tumor-associated NF-kappaB activity. Quantitation of proliferation, apoptosis, and interleukin 6 (IL-6) and IL-10 secretion by tumor cells in culture revealed that the effects of PS-341 on cell growth largely correlated with inhibition of pathways mediated by NF-kappaB. However, the effect of PS-341 on the growth of tumors in Tax transgenic mice revealed heterogeneity in drug responsiveness. The tumor tissues treated with PS-341 show no consistent inhibition of NFkappaB activation in vivo. Annexin V staining indicated that PS-341 response in vivo correlated with sensitivity to apoptosis induced by gamma irradiation. On the other hand, transplanted Tax tumors in Rag-1 mice showed consistent inhibition of tumor growth and prolonged survival in response to the same drug regimen. TUNEL staining indicated that PS-341 treatment sensitizes Tax tumors to DNA fragmentation.
Mitra-Kaushik
Shibani
S
Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Harding
John C
JC
Hess
Jay L
JL
Ratner
Lee
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D003433:Crosses, Genetic; D003546:Cysteine Endopeptidases; D004261:DNA Replication / Q000187:drug effects; D016355:Genes, pX; D015490:HTLV-I Infections / Q000276:immunology / Q000473:pathology*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D015850:Interleukin-6; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D016753:Interleukin-10; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex