Synergistic activity of letrozole and sorafenib on breast cancer cells.
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.
Bonelli
Mara A
MA
Department of Experimental Medicine, University of Parma, Via Volturno 39, 43100 Parma, Italy.
Fumarola
Claudia
C
Alfieri
Roberta R
RR
La Monica
Silvia
S
Cavazzoni
Andrea
A
Galetti
Maricla
M
Gatti
Rita
R
Belletti
Silvana
S
Harris
Adrian L
AL
Fox
Stephen B
SB
Evans
Dean B
DB
Dowsett
Mitch
M
Martin
Lesley-Ann
LA
Bottini
Alberto
A
Generali
Daniele
D
Petronini
Pier Giorgio
PG
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D000077289:Letrozole; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009536:Niacinamide / Q000031:analogs & derivatives; D009570:Nitriles / Q000494:pharmacology; D010671:Phenylurea Compounds; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology
C494829:AIFM1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051033:Apoptosis Inducing Factor; D047072:Aromatase Inhibitors; D001557:Benzenesulfonates; C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C489427:MYC protein, human; D046912:Multiprotein Complexes; D009570:Nitriles; D010671:Phenylurea Compounds; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D016160:Retinoblastoma Protein; D014230:Triazoles; D019938:Cyclin D1; D009536:Niacinamide; D013739:Testosterone; D004958:Estradiol; D000077289:Letrozole; D045304:Cytochromes c; D000077157:Sorafenib; D001141:Aromatase; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C505520:CASP7 protein, human; C506433:CASP9 protein, human; D053179:Caspase 7; D053453:Caspase 9