Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling.
BACKGROUND
Imatinib mesylate is a tyrosine kinase receptor inhibitor targeted against PDGFR alpha and beta, c-kit and bcr-abl. These receptors regulate cellular processes such as proliferation, differentiation, and survival. This study was performed to evaluate the effects of imatinib on breast cancer cell lines with respect to the activity of PDGFR beta and Akt: a downstream modulator of cell growth and survival.


METHODS
Expression of imatinib targets was analyzed with reverse transciptase PCR and immunoblotting assays in the breast cell lines MDA MB 231, MCF 7, ZR 75-1, and T 47-D. Changes on receptor expression and phosphorylation status under imatinib were evaluated using drug concentrations of 2 to 10 microM. The anti-proliferative and pro-apoptotic effects of imatinib alone and in combination with vinorelbine were investigated with an MTT and TUNEL assay.


RESULTS
Imatinib inhibited growth and induced apoptosis of all cell lines examined. This effect was increased when combined with vinorelbine. A dose-dependent inhibitory effect on the phosphorylation of PDGFR beta and Akt was detected.


CONCLUSIONS
The growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR beta and Akt. Imatinib is a promising novel drug for targeted therapy of breast cancer patients.
Weigel
Marion T
MT
Department of Obstetrics and Gynecology, Breast Center, University Hospital Schleswig-Holstein, Campus Kiel, Michaelisstrasse 16, 24105 Kiel, Germany. wweigel22@aol.com
Meinhold-Heerlein
Ivo
I
Bauerschlag
Dirk O
DO
Schem
Christian
C
Bauer
Maret
M
Jonat
Walter
W
Maass
Nicolai
N
Mundhenke
Christoph
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D007150:Immunohistochemistry; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D014747:Vinblastine; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D051058:Oncogene Protein v-akt; D000077235:Vinorelbine