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The vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 inhibits aromatase

Susana Banerjee1, Marketa Zvelebil, Pascal Furet

  • 1Breakthrough Breast Cancer Research Centre, Institute of Cancer Research. London, SW3 6JB, United Kingdom.

Cancer Research
|May 14, 2009
PubMed

Insights

The study found that PTK787/ZK222584 (PTK/ZK), an antiangiogenic agent, unexpectedly inhibits aromatase activity. This dual inhibition of vascular endothelial growth factor receptor (VEGFR) and aromatase suggests potential for new breast cancer therapies.

Area of Science:

  • Oncology
  • Endocrinology
  • Pharmacology

Background:

  • Endocrine therapy and antiangiogenic agents are key breast cancer treatments.
  • Concomitant targeting of vascular endothelial growth factor (VEGF) and estrogen receptor (ER) pathways may improve outcomes in ER-positive breast cancer.

Purpose of the Study:

  • To investigate the effects of the VEGF receptor (VEGFR) inhibitor PTK787/ZK222584 (PTK/ZK) on human breast cancer cell lines engineered to express aromatase.
  • To determine if PTK/ZK exhibits antiaromatase activity and explore its potential as a dual-target inhibitor.

Main Methods:

  • Utilized human breast cancer cell lines engineered to express aromatase.
  • Administered estrogen (E2) or androstenedione with or without PTK/ZK.
  • Assessed cell proliferation and ER-mediated transcription.
  • Performed computer-assisted molecular modeling to predict PTK/ZK binding to aromatase.

Main Results:

  • Androstenedione stimulated proliferation and ER-mediated transcription, as expected.
  • PTK/ZK unexpectedly suppressed androstenedione-stimulated proliferation and ER-mediated transcription.
  • PTK/ZK demonstrated antiaromatase activity, acting as a competitive inhibitor.
  • Molecular modeling suggested direct binding of PTK/ZK to aromatase.

Conclusions:

  • PTK/ZK possesses previously unrecognized antiaromatase activity.
  • PTK/ZK acts as a competitive inhibitor of aromatase.
  • Agents that cross-inhibit both VEGFR and aromatase represent a promising therapeutic strategy for breast cancer.

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