Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line

Melinda M. Mortenson, Michael G. Schlieman, Subbulakshmi Virudachalam, Richard J Bold

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Background: Non-small-cell lung cancer (NSCLC) has a poor prognosis. Despite advances in therapy, survival has improved only slightly. The 26S proteasome regulates multiple cellular processes through degradation of ubiquitin-tagged proteins. The proteasome inhibitor, bortezomib (Velcade, formerly PS-341), has been shown to be an active anticancer agent both in vitro and in vivo in multiple tumor types. Purpose: To determine the molecular and cellular effects of the proteasome inhibitor in NSCLC as well as to evaluate the effectiveness of sequential treatment with bortezomib and gemcitabine/ carboplatin (G/C) chemotherapy both in vitro and in vivo. Methods: All experiments were performed in the A549 NSCLC cell line. MTT assays were used to evaluate cytotoxicity. Western blotting evaluated protein levels. Measures of apoptosis included FACS analysis, DAPI staining and caspase-3 cleavage. Long-term cell viability was determined using an anchorage-dependent clonogenic assay. Sequential studies were performed in vitro and in vivo. Results: Bortezomib increased p21waf1/cip1, induced G2/M arrest, and triggered a small amount of apoptosis. The apoptotic effect of G/C chemotherapy was eliminated when bortezomib was administered prior to the chemotherapy; however, it was accentuated when the bortezomib was given simultaneously or after the chemotherapy. Conclusions: Bortezomib improves efficacy in combination with gemcitabine and carboplatin in NSCLC, but sequential effects are important and must be considered when developing therapeutic regimens.

Original languageEnglish (US)
Pages (from-to)343-353
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume54
Issue number4
DOIs
StatePublished - Oct 2004

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Proteasome Inhibitors
Chemotherapy
Combination Drug Therapy
Non-Small Cell Lung Carcinoma
gemcitabine
Cells
Cell Line
Carboplatin
Drug Therapy
Assays
Apoptosis
Bortezomib
Cytotoxicity
Ubiquitin
Caspase 3
Antineoplastic Agents
Tumors
Cell Survival
Proteins
Western Blotting

Keywords

  • Apoptosis
  • Bortezomib
  • Lung cancer
  • p21
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line. / Mortenson, Melinda M.; Schlieman, Michael G.; Virudachalam, Subbulakshmi; Bold, Richard J.

In: Cancer Chemotherapy and Pharmacology, Vol. 54, No. 4, 10.2004, p. 343-353.

Research output: Contribution to journalArticle

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