The vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 inhibits aromatase.
Endocrine therapy is well established for the treatment of breast cancer, and antiangiogenic agents are showing considerable promise. Targeting the vascular endothelial growth factor (VEGF) and estrogen receptor (ER) signaling pathways concomitantly may provide enhanced therapeutic benefit in ER-positive breast cancer. Therefore, the effects of the VEGF receptor (VEGFR) tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) were investigated using human breast cancer cell lines engineered to express aromatase. As expected in this system, estrogen (E2) or androstenedione induced a proliferative response and increased ER-mediated transcription in ER-positive cell lines expressing aromatase. However, surprisingly, in the presence of androstenedione, PTK/ZK suppressed both the androstenedione-stimulated proliferation and ER-mediated transcription. PTK/ZK alone and in the presence of E2 had no observable effect on proliferation or ER-mediated transcription. These effects result from PTK/ZK having previously unrecognized antiaromatase activity and PTK/ZK being a competitive aromatase inhibitor. Computer-assisted molecular modeling showed that PTK/ZK could potentially bind directly to aromatase. The demonstration that PTK/ZK inhibits aromatase and VEGFR indicates that agents cross-inhibiting two important classes of targets in breast cancer could be developed.
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research. London, SW3 6JB, United Kingdom.
Susana
S
Banerjee
Marketa
M
Zvelebil
Pascal
P
Furet
Ursula
U
Mueller-Vieira
Dean B
DB
Evans
Mitch
M
Dowsett
Lesley-Ann
LA
Martin
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D010793:Phthalazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D047072:Aromatase Inhibitors; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011960:Receptors, Estrogen; D004958:Estradiol; C404768:vatalanib; D001141:Aromatase; D040262:Receptors, Vascular Endothelial Growth Factor