Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models.
Treatment options are insufficient in patients with adrenocortical carcinoma (ACC). Based on the efficacy of sorafenib, a tyrosine kinase inhibitor, and everolimus, an inhibitor of the mammalian target of rapamycin in tumors of different histotype, we aimed at testing these drugs in adrenocortical cancer models. The expression of vascular endothelial growth factor and its receptors (VEGFR1-2) was studied in 18 ACCs, 33 aldosterone-producing adenomas, 12 cortisol-producing adenomas, and six normal adrenal cortex by real-time PCR and immunohistochemistry and by immunoblotting in SW13 and H295R cancer cell lines. The effects of sorafenib and everolimus, alone or in combination, were tested on primary adrenocortical cultures and SW13 and H295R cells by evaluating cell viability and apoptosis in vitro and tumor growth inhibition of tumor cell line xenografts in immunodeficient mice in vivo. VEGF and VEGFR1-2 were detected in all samples and appeared over-expressed in two-thirds of ACC specimens. Dose-dependent inhibition of cell viability was observed particularly in SW13 cells after 24 h treatment with either drug; drug combination produced markedly synergistic growth inhibition. Increasing apoptosis was observed in tumor cells treated with the drugs, particularly with sorafenib. Finally, a significant mass reduction and increased survival were observed in SW13 xenograft model undergoing treatment with the drugs in combination. Our data suggest that an autocrine VEGF loop may exist within ACC. Furthermore, a combination of molecularly targeted agents may have both antiangiogenic and direct antitumor effects and thus could represent a new therapeutic tool for the treatment of ACC.
Endocrinology Unit, Department of Medicine, University of Padua, Via Ospedale Civile 105, 35128 Padua, Italy.
Barbara
B
Mariniello
Antonio
A
Rosato
Gaia
G
Zuccolotto
Beatrice
B
Rubin
Maria Verena
MV
Cicala
Isabella
I
Finco
Maurizio
M
Iacobone
Anna Chiara
AC
Frigo
Ambrogio
A
Fassina
Raffaele
R
Pezzani
Franco
F
Mantero
D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology; D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D000068338:Everolimus; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077157:Sorafenib; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D020123:Sirolimus