The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo

Ashish M. Kamat, Takashi Karashima, Darren W. Davis, Laura Lashinger, Menashe Bar-Eli, Randall Millikan, Yu Shen, Colin P.N. Dinney, David J. McConkey

Research output: Contribution to journalArticle

Abstract

Bortezomib (PS-341, Velcade) is a dipeptidyl boronic acid inhibitor of the 20S proteasome that was developed as a therapeutic agent for cancer. Here, we investigated the effects of bortezomib on the growth of human 253JB-V bladder cancer cells. Although the drug did not stimulate significant increases in levels of apoptosis, it inhibited cell growth in a concentration-dependent fashion and augmented the growth inhibitory effects of gemcitabine in vitro. These effects were associated with accumulation of p53 and p21 and suppression of cyclin-dependent kinase 2 activity. Bortezomib also inhibited secretion of the proangiogenic factors matrix metalloproteinase-9, interieukin-8 (IL-8), and vascular endothelial growth factor (VEGF). In vivo studies with 253JB-V tumors growing in nude mice demonstrated that bortezomib (1 mg/kg) did not inhibit tumor growth when it was delivered as a single agent, although it reduced tumor microvessel density and inhibited expression of VEGF and IL-8. However, combination therapy with bortezomib plus gemcitabine produced synergistic tumor growth inhibition associated with strong suppression of tumor cell proliferation. Together, our results demonstrate that bortezomib has significant antiproliferative activity in aggressive bladder cancer cells, which is best exploited within the context of combination chemotherapy.

Original languageEnglish (US)
Pages (from-to)279-290
Number of pages12
JournalMolecular cancer therapeutics
Volume3
Issue number3
StatePublished - Mar 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Kamat, A. M., Karashima, T., Davis, D. W., Lashinger, L., Bar-Eli, M., Millikan, R., Shen, Y., Dinney, C. P. N., & McConkey, D. J. (2004). The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo. Molecular cancer therapeutics, 3(3), 279-290.