Flavopiridol blocks integrin-mediated survival in dormant breast cancer cells.
OBJECTIVE
Breast cancer micrometastases in the bone marrow are resistant to chemotherapy. They can remain dormant for years before some begin to proliferate. We seek to understand survival mechanisms and develop targeted approaches to eliminating these cells.


METHODS
In an in vitro model of dormancy, basic fibroblast growth factor 2 (FGF-2), abundant in the bone marrow, inhibits the growth of well-differentiated cells in the 2- to 10-cell stage and up-regulates integrin alpha(5)beta(1). Through this integrin, cells bind fibronectin, spread out, and acquire a survival advantage, partly through activation of the phosphatidylinositol 3-kinase/Akt pathway. We investigated the effects of Taxotere, flavopiridol, and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and p38 inhibitors on survival of dormant clones and that of flavopiridol on expression of integrins, adhesion strength, and phosphorylation of Akt, ERK 1/2, and p38.


RESULTS
Dormant MCF-7 and T-47D cell clones were resistant to Taxotere concentrations 10-fold higher than needed to eliminate growing clones but were almost completely eradicated by 200 nmol/L flavopiridol. Flavopiridol caused a decrease in FGF-2-induced expression of integrins, including alpha(5) and beta(1), and decreased FGF-2-induced specific adhesion to fibronectin. It diminished Akt phosphorylation, but reexpression of active Akt was not sufficient to reverse dormant clone inhibition. Flavopiridol did not affect phosphorylation of ERK 1/2 and p38 but diminished total protein levels. Chemical inhibition of these pathways partially abrogated dormant clone survival.


CONCLUSIONS
Flavopiridol has pleiotropic effects on key targets involved with survival of dormant breast cancer cells and may represent a useful approach to eliminating cells dependent on multiple signal pathways for survival.
Najmi
Saltanat
S
Division of Oncology/Hematology, Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA.
Korah
Reju
R
Chandra
Rachna
R
Abdellatif
Maha
M
Wieder
Robert
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001853:Bone Marrow / Q000502:physiology; D001859:Bone Neoplasms / Q000503:physiopathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D002470:Cell Survival; D000077143:Docetaxel; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D010880:Piperidines; D043823:Taxoids; D016222:Fibroblast Growth Factor 2; D000077143:Docetaxel; C077990:alvocidib; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases