Imatinib Mesylate (Gleevec) Inhibits Ovarian Cancer Cell Growth through a Mechanism Dependent on Platelet-Derived Growth Factor Receptor α and Akt Inactivation

Daniela Matei, David D. Chang, Meei Huey Jeng

Research output: Contribution to journalArticle

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Abstract

Purpose: We identified the platelet-derived growth factor receptor α (PDGFRα) as an ovarian cancer-specific gene by microarray hybridization using primary cultures. The purpose of this study is to evaluate whether disruption of the platelet-derived growth factor-regulated growth pathway by Imatinib mesylate (Gleevec), a partially selective PDGFR inhibitor, inhibits growth of ovarian cancer cells expressing PDGFR. Experimental Design: To investigate the effects of Imatinib mesylate in ovarian cancer, we established an in vitro model by immortalizing primary ovarian cells, which express endogenous PDGFR, and we evaluated the effects of Imatinib on cell proliferation. In addition, we investigated the involvement of Akt in mediating Imatinib-inhibited cell growth inhibition. Results: We found that 39% of ovarian tumors express PDGFR by immunohistochemistry. We showed that Imatinib inhibits the growth of ovarian cancer cells in a PDGFR-specific manner, at clinically relevant concentrations (IC50 < 1 μM). Imatinib inhibits the growth of three primary ovarian cultures and two immortalized cultures (PDGFR positive), but has no effects on SkOv3 and CaOv3 cell lines (PDGFR negative). Imatinib exerts antiproliferative effects by arresting cells at G0-G1 and preventing progression through S phase. Imatinib inhibits both PDGFRα and Akt phosphorylation at a concentration of 1 μM. Stable expression of constitutively active Akt induces partial resistance to PDGFR inhibition in ovarian cancer cells, as demonstrated by cell proliferation assay and cell cycle analysis. Conclusions: Our data indicate that Imatinib mesylate inhibits the growth of ovarian cancer cells through PDGFR inactivation. In addition, our results suggest that constitutive Akt activation modulates sensitivity to Imatinib in ovarian cancer cells.

Original languageEnglish
Pages (from-to)681-690
Number of pages10
JournalClinical Cancer Research
Volume10
Issue number2
DOIs
StatePublished - Jan 15 2004

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Platelet-Derived Growth Factor Receptors
Ovarian Neoplasms
Growth
Imatinib Mesylate
Cell Proliferation
Growth Inhibitors
Neoplasm Genes
Platelet-Derived Growth Factor
S Phase
Inhibitory Concentration 50
Cell Cycle
Research Design
Immunohistochemistry
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Imatinib Mesylate (Gleevec) Inhibits Ovarian Cancer Cell Growth through a Mechanism Dependent on Platelet-Derived Growth Factor Receptor α and Akt Inactivation. / Matei, Daniela; Chang, David D.; Jeng, Meei Huey.

In: Clinical Cancer Research, Vol. 10, No. 2, 15.01.2004, p. 681-690.

Research output: Contribution to journalArticle

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abstract = "Purpose: We identified the platelet-derived growth factor receptor α (PDGFRα) as an ovarian cancer-specific gene by microarray hybridization using primary cultures. The purpose of this study is to evaluate whether disruption of the platelet-derived growth factor-regulated growth pathway by Imatinib mesylate (Gleevec), a partially selective PDGFR inhibitor, inhibits growth of ovarian cancer cells expressing PDGFR. Experimental Design: To investigate the effects of Imatinib mesylate in ovarian cancer, we established an in vitro model by immortalizing primary ovarian cells, which express endogenous PDGFR, and we evaluated the effects of Imatinib on cell proliferation. In addition, we investigated the involvement of Akt in mediating Imatinib-inhibited cell growth inhibition. Results: We found that 39{\%} of ovarian tumors express PDGFR by immunohistochemistry. We showed that Imatinib inhibits the growth of ovarian cancer cells in a PDGFR-specific manner, at clinically relevant concentrations (IC50 < 1 μM). Imatinib inhibits the growth of three primary ovarian cultures and two immortalized cultures (PDGFR positive), but has no effects on SkOv3 and CaOv3 cell lines (PDGFR negative). Imatinib exerts antiproliferative effects by arresting cells at G0-G1 and preventing progression through S phase. Imatinib inhibits both PDGFRα and Akt phosphorylation at a concentration of 1 μM. Stable expression of constitutively active Akt induces partial resistance to PDGFR inhibition in ovarian cancer cells, as demonstrated by cell proliferation assay and cell cycle analysis. Conclusions: Our data indicate that Imatinib mesylate inhibits the growth of ovarian cancer cells through PDGFR inactivation. In addition, our results suggest that constitutive Akt activation modulates sensitivity to Imatinib in ovarian cancer cells.",
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