Synergistic activity of letrozole and sorafenib on breast cancer cells.

Abstract	Estrogens induce breast tumor cell proliferation by directly regulating gene expression via the estrogen receptor (ER) transcriptional activity and by affecting growth factor signaling pathways such as mitogen-activated protein kinase (MAPK) and AKT/mammalian target of rapamycin Complex1 (mTORC1) cascades. In this study we demonstrated the preclinical therapeutic efficacy of combining the aromatase inhibitor letrozole with the multi-kinase inhibitor sorafenib in aromatase-expressing breast cancer cell lines. Treatment with letrozole reduced testosterone-driven cell proliferation, by inhibiting the synthesis of estrogens. Sorafenib inhibited cell proliferation in a concentration-dependent manner; this effect was not dependent on sorafenib-mediated inhibition of Raf1, but involved the down-regulation of mTORC1 and its targets p70S6K and 4E-binding protein 1 (4E-BP1). At concentrations of 5-10 μM the growth-inhibitory effect of sorafenib was associated with the induction of apoptosis, as indicated by release of cytochrome c and Apoptosis-Inducing Factor into the cytosol, activation of caspase-9 and caspase-7, and PARP-1 cleavage. Combination of letrozole and sorafenib produced a synergistic inhibition of cell proliferation associated with an enhanced accumulation of cells in the G(0)/G(1) phase of the cell cycle and with a down-regulation of the cell cycle regulatory proteins c-myc, cyclin D1, and phospho-Rb. In addition, longer experiments (12 weeks) demonstrated that sorafenib may be effective in preventing the acquisition of resistance towards letrozole. Together, these results indicate that combination of letrozole and sorafenib might constitute a promising approach to the treatment of hormone-dependent breast cancer.
Authors	Mara A Bonelli, Claudia Fumarola, Roberta R Alfieri, Silvia La Monica, Andrea Cavazzoni, Maricla Galetti, Rita Gatti, Silvana Belletti, Adrian L Harris, Stephen B Fox, Dean B Evans, Mitch Dowsett, Lesley-Ann Martin, Alberto Bottini, Daniele Generali, Pier Giorgio Petronini
Journal	Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 124 Issue 1 Pg. 79-88 (Nov 2010) ISSN: 1573-7217 [Electronic] Netherlands
PMID	20054642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	AIFM1 protein, human Adaptor Proteins, Signal Transducing Apoptosis Inducing Factor Aromatase Inhibitors Benzenesulfonates CCND1 protein, human Cell Cycle Proteins EIF4EBP1 protein, human MYC protein, human Multiprotein Complexes Nitriles Phenylurea Compounds Phosphoproteins Protein Kinase Inhibitors Proteins Proto-Oncogene Proteins c-myc Pyridines Retinoblastoma Protein Triazoles Cyclin D1 Niacinamide Testosterone Estradiol Letrozole Cytochromes c Sorafenib Aromatase PARP1 protein, human Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases Mechanistic Target of Rapamycin Complex 1 Ribosomal Protein S6 Kinases, 70-kDa TOR Serine-Threonine Kinases CASP7 protein, human CASP9 protein, human Caspase 7 Caspase 9
Topics	Adaptor Proteins, Signal Transducing (metabolism) Antineoplastic Combined Chemotherapy Protocols (pharmacology) Apoptosis (drug effects) Apoptosis Inducing Factor (metabolism) Aromatase (genetics, metabolism) Aromatase Inhibitors (pharmacology) Benzenesulfonates (pharmacology) Breast Neoplasms (enzymology, genetics, pathology) Caspase 7 (metabolism) Caspase 9 (metabolism) Cell Cycle (drug effects) Cell Cycle Proteins Cell Line, Tumor Cell Proliferation (drug effects) Cyclin D1 (metabolism) Cytochromes c (metabolism) Dose-Response Relationship, Drug Drug Resistance, Neoplasm Drug Synergism Estradiol (metabolism) Female Humans Letrozole Mechanistic Target of Rapamycin Complex 1 Multiprotein Complexes Niacinamide (analogs & derivatives) Nitriles (pharmacology) Phenylurea Compounds Phosphoproteins (metabolism) Phosphorylation Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases (metabolism) Protein Kinase Inhibitors (pharmacology) Proteins (metabolism) Proto-Oncogene Proteins c-myc (metabolism) Pyridines (pharmacology) Retinoblastoma Protein (metabolism) Ribosomal Protein S6 Kinases, 70-kDa (metabolism) Sorafenib TOR Serine-Threonine Kinases Testosterone (metabolism) Time Factors Transfection Triazoles (pharmacology)

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