Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants

Shibani Mitra-Kaushik, John C. Harding, Jay Hess, Lee Ratner

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Recent studies have shown that the transcription factor nuclear factor κB (NF-κB) 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-κB is controlled by proteasome-mediated degradation of the inhibitor of nuclear factor κBα (IκBα). 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-κB 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-κB. 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 NFκB activation in vivo. Annexin V staining indicated that PS-341 response in vivo correlated with sensitivity to apoptosis induced by γ 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.

Original languageEnglish (US)
Pages (from-to)802-809
Number of pages8
JournalBlood
Volume104
Issue number3
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

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Deltaretrovirus
Transplants
Proteasome Inhibitors
T-cells
Taxation
Viruses
Transgenic Mice
Tumors
Growth
Neoplasms
Chemical activation
Apoptosis
Staining and Labeling
Bortezomib
Annexin A5
Cell growth
Corrosion inhibitors
Critical Pathways
Proteasome Endopeptidase Complex
Cell culture

ASJC Scopus subject areas

  • Hematology

Cite this

Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants. / Mitra-Kaushik, Shibani; Harding, John C.; Hess, Jay; Ratner, Lee.

In: Blood, Vol. 104, No. 3, 01.08.2004, p. 802-809.

Research output: Contribution to journalArticle

Mitra-Kaushik, Shibani ; Harding, John C. ; Hess, Jay ; Ratner, Lee. / Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants. In: Blood. 2004 ; Vol. 104, No. 3. pp. 802-809.
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