The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor zenografts

Stefan T. Nawrocki, Bridget Sweeney-Gotsch, Ryan Takamori, David McConkey

Research output: Contribution to journalArticle

Abstract

Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative, which is a selective and potent inhibitor of the proteasome. We examined the antitumor activity of combination therapy with bortezomib + docetaxel in two human pancreatic cancer cell lines (MiaPaCa-2 and L3.6pl) selected for their divergent responses to bortezomib alone. Bortezomib blocked docetaxel-induced apoptosis in the MiaPaCa-2 cells and failed to enhance docetaxel-induced apoptosis in L3.6pl cells in vitro but did interact positively with docetaxel to inhibit clonogenic survival. These effects were associated with decreased accumulation of cells in M phase, stabilization of the cyclin-dependent kinase inhibitors, p21 and p27, and inhibition of cdk2 and cdc2 activities. In orthotopic xenografts, combination therapy produced significant reductions in tumor weight and volume in both models associated with accumulation of p21, inhibition of proliferation, and increased apoptosis. Combination therapy also reduced tumor microvessel densities, effects that were associated with reductions in tumor cell production of vascular endothelial growth factor and increased levels of apoptosis in tumor-associated endothelial cells. Together, our results suggest that bortezomib enhances the antitumoral activity of taxanes by enforcing cell growth arrest and inhibiting angiogenesis.

Original languageEnglish (US)
Pages (from-to)59-70
Number of pages12
JournalMolecular Cancer Therapeutics
Volume3
Issue number1
StatePublished - Jan 2004
Externally publishedYes

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docetaxel
Proteasome Inhibitors
Neoplasms
Apoptosis
Tumor Burden
Boronic Acids
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Taxoids
Dipeptides
Microvessels
Bortezomib
Pancreatic Neoplasms
Heterografts
Cell Division
Vascular Endothelial Growth Factor A
Therapeutics
Endothelial Cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor zenografts. / Nawrocki, Stefan T.; Sweeney-Gotsch, Bridget; Takamori, Ryan; McConkey, David.

In: Molecular Cancer Therapeutics, Vol. 3, No. 1, 01.2004, p. 59-70.

Research output: Contribution to journalArticle

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