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The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells.

Voortman J, Checińska A, Giaccone G - Mol. Cancer (2007)

Bottom Line: However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis.Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis.In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology, VU University Medical Center, 1081HV Amsterdam, the Netherlands. j.voortman@vumc.nl

ABSTRACT
Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms.

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Growth inhibition by bortezomib in NSCLC cells. (A) Growth curves (MTT assays) of NSCLC cells treated with different concentrations of bortezomib. Mean of at least three independent experiments, SD. (B) IC50 concentrations and p53 status of individual cell lines. Wt: wild type; mut: mutated.
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Figure 1: Growth inhibition by bortezomib in NSCLC cells. (A) Growth curves (MTT assays) of NSCLC cells treated with different concentrations of bortezomib. Mean of at least three independent experiments, SD. (B) IC50 concentrations and p53 status of individual cell lines. Wt: wild type; mut: mutated.

Mentions: We first determined the anti-proliferative effect of a concentration range of bortezomib by MTT assay in a panel of NSCLC cell lines (Figure 1A). We observed differential sensitivity to bortezomib-induced growth inhibition, with IC50 values ranging from 5 to 83 nM. The p53 status did not correlate with sensitivity (Figure 1B). Next, to establish the apoptosis inducing potential of bortezomib, a sensitive cell line, SW1573, and a resistant cell line, H460, were selected for treatment and subsequent PI staining-based FACS analysis to determine the subG1 apoptotic fraction of the cell population. Additionally, the fractions of cells in the G1, S or G2M phase of the cell cycle were assessed.


The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells.

Voortman J, Checińska A, Giaccone G - Mol. Cancer (2007)

Growth inhibition by bortezomib in NSCLC cells. (A) Growth curves (MTT assays) of NSCLC cells treated with different concentrations of bortezomib. Mean of at least three independent experiments, SD. (B) IC50 concentrations and p53 status of individual cell lines. Wt: wild type; mut: mutated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2194734&req=5

Figure 1: Growth inhibition by bortezomib in NSCLC cells. (A) Growth curves (MTT assays) of NSCLC cells treated with different concentrations of bortezomib. Mean of at least three independent experiments, SD. (B) IC50 concentrations and p53 status of individual cell lines. Wt: wild type; mut: mutated.
Mentions: We first determined the anti-proliferative effect of a concentration range of bortezomib by MTT assay in a panel of NSCLC cell lines (Figure 1A). We observed differential sensitivity to bortezomib-induced growth inhibition, with IC50 values ranging from 5 to 83 nM. The p53 status did not correlate with sensitivity (Figure 1B). Next, to establish the apoptosis inducing potential of bortezomib, a sensitive cell line, SW1573, and a resistant cell line, H460, were selected for treatment and subsequent PI staining-based FACS analysis to determine the subG1 apoptotic fraction of the cell population. Additionally, the fractions of cells in the G1, S or G2M phase of the cell cycle were assessed.

Bottom Line: However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis.Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis.In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology, VU University Medical Center, 1081HV Amsterdam, the Netherlands. j.voortman@vumc.nl

ABSTRACT
Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms.

Show MeSH
Related in: MedlinePlus