RT Journal Article
SR Electronic
T1 Transcriptome Analysis and In Vivo Activity of Fluvastatin versus Zoledronic Acid in a Murine Breast Cancer Metastasis Model
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 521
OP 528
DO 10.1124/mol.111.077248
VO 82
IS 3
A1 Nadejda Vintonenko
A1 Jean-Philippe Jais
A1 Nadim Kassis
A1 Mohamed Abdelkarim
A1 Gerard-Yves Perret
A1 Marc Lecouvey
A1 Michel Crepin
A1 Melanie Di Benedetto
YR 2012
UL http://molpharm.aspetjournals.org/content/82/3/521.abstract
AB Statins and bisphosphonates are two distinct classes of isoprenoid pathway inhibitors targeting downstream enzyme to HMG-CoA reductase (upstream enzyme) and farnesyl-pyrophosphate synthase, respectively. Here, we studied fluvastatin (Fluva) and zoledronate (Zol), representative molecules of each class, respectively. In vivo metastatic potentials of both molecules were assessed. For the first time, we observed a significant reduction in progression of established metastases with Fluva treatment. Treatment with both Zol at 100 μg/kg and Fluva at 15 mg/kg inhibited 80% of the metastasis bioluminescence signal and increased survival of mice. The Zol and Fluva transcriptomic profiles of treated MDA-MB-231 cells revealed analogous patterns of affected genes, but each of them reached with different kinetics. The observable changes in gene expression started after 24 h for Fluva IC50 72 h and only after 48 h for Zol IC50 72 h. To obtain early changes in gene expression of Zol-treated cells, a 3 times higher dose of Zol IC50 72 h had to be applied. Combining Fluva and Zol in vivo showed no synergy, but a benefit of several days in survival of mice. This study demonstrated that Zol or Fluva is of potential clinical use for the treatment of established metastasis.