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Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro.

Zhang P, Gao WY, Turner S, Ducatman BS - Mol. Cancer (2003)

Bottom Line: Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells.We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology & Cancer Center, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV 26506-9203, USA. pzhang@hsc.wvu.edu

ABSTRACT

Background: Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer.

Results: We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2-3 microM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 microM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor alpha, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR alpha phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-alpha expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.

Conclusion: These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

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Related in: MedlinePlus

Western blot analyses of PDGFR-α in the whole A549 cell lysates. The whole cell lysates were separated on 7.5% SDS-PAGE and analyzed by Western blot using anti-PDGFR-α antibody. Treatment of A549 cells with Gleevec showed no effect on the PDGFR-α protein expression.
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Figure 8: Western blot analyses of PDGFR-α in the whole A549 cell lysates. The whole cell lysates were separated on 7.5% SDS-PAGE and analyzed by Western blot using anti-PDGFR-α antibody. Treatment of A549 cells with Gleevec showed no effect on the PDGFR-α protein expression.

Mentions: Since the effect of Gleevec is mediated through inhibiting BCR-ABL tyrosine kinase, c-kit, and PDGF receptors, we are interested in the potential target for Gleevec effect in the lung cancer cells. We have previously showed by immunohistochemical staining that in 54 primary non-small cell lung carcinoma specimens, expression of c-kit was weak and minimal, if any (Tang and Zhang, unpublished observation). We sought to determine the expression levels of PDGF receptors α and β in A549 cells and the primary non-small cell lung carcinoma by immunofluorescent and immunohistochemical staining methods. In A549 cells, expression of PDGFR-α, not PDGFR-β, was detected with strong cytoplasmic and membrane staining patterns (Figure 6 and 7). There was no demonstrable nuclear staining signal. We further detected the presence of PDGFR-α in the whole cell lysates of A549 cells by Western blotting analysis (Figure 8). A549 cells were cultured under the condition described, and the cells were lysed and the whole cell proteins were separated on 7.5% SDS-PAGE. The proteins were transferred onto nitrocellulose membrane, and the PDGFR-α was detected with anti-PDGFR-α antibody (Santa Cruz Biotechnologies Inc.). Treatment of the cells with Gleevec at two concentrations did not influence the expression of PDGFR-α expression in the cells. PDGFR-β was not detected in A549 cells using both immunofluorescent staining and Western blot analyses (Data not shown).


Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro.

Zhang P, Gao WY, Turner S, Ducatman BS - Mol. Cancer (2003)

Western blot analyses of PDGFR-α in the whole A549 cell lysates. The whole cell lysates were separated on 7.5% SDS-PAGE and analyzed by Western blot using anti-PDGFR-α antibody. Treatment of A549 cells with Gleevec showed no effect on the PDGFR-α protein expression.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC149413&req=5

Figure 8: Western blot analyses of PDGFR-α in the whole A549 cell lysates. The whole cell lysates were separated on 7.5% SDS-PAGE and analyzed by Western blot using anti-PDGFR-α antibody. Treatment of A549 cells with Gleevec showed no effect on the PDGFR-α protein expression.
Mentions: Since the effect of Gleevec is mediated through inhibiting BCR-ABL tyrosine kinase, c-kit, and PDGF receptors, we are interested in the potential target for Gleevec effect in the lung cancer cells. We have previously showed by immunohistochemical staining that in 54 primary non-small cell lung carcinoma specimens, expression of c-kit was weak and minimal, if any (Tang and Zhang, unpublished observation). We sought to determine the expression levels of PDGF receptors α and β in A549 cells and the primary non-small cell lung carcinoma by immunofluorescent and immunohistochemical staining methods. In A549 cells, expression of PDGFR-α, not PDGFR-β, was detected with strong cytoplasmic and membrane staining patterns (Figure 6 and 7). There was no demonstrable nuclear staining signal. We further detected the presence of PDGFR-α in the whole cell lysates of A549 cells by Western blotting analysis (Figure 8). A549 cells were cultured under the condition described, and the cells were lysed and the whole cell proteins were separated on 7.5% SDS-PAGE. The proteins were transferred onto nitrocellulose membrane, and the PDGFR-α was detected with anti-PDGFR-α antibody (Santa Cruz Biotechnologies Inc.). Treatment of the cells with Gleevec at two concentrations did not influence the expression of PDGFR-α expression in the cells. PDGFR-β was not detected in A549 cells using both immunofluorescent staining and Western blot analyses (Data not shown).

Bottom Line: Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells.We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology & Cancer Center, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV 26506-9203, USA. pzhang@hsc.wvu.edu

ABSTRACT

Background: Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer.

Results: We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2-3 microM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 microM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor alpha, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR alpha phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-alpha expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.

Conclusion: These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

Show MeSH
Related in: MedlinePlus