| First Author | Mitra-Kaushik S | Year | 2004 |
| Journal | Blood | Volume | 104 |
| Issue | 3 | Pages | 802-9 |
| PubMed ID | 15090453 | Mgi Jnum | J:92261 |
| Mgi Id | MGI:3052275 | Doi | 10.1182/blood-2003-11-3967 |
| Citation | Mitra-Kaushik S, et al. (2004) Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants. Blood 104(3):802-9 |
| abstractText | 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. |
