Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo.
BACKGROUND
Uterine sarcomas are very rare malignancies with no approved chemotherapy protocols. Histone deacetylase (HDAC) inhibitors belong to the most promising groups of compounds for molecular targeting therapy. Here, we described the antitumor effects of suberoylanilide hydroxamic acid (SAHA; vorinostat) on MES-SA uterine sarcoma cells in vitro and in vivo. We investigated effects of vorinostat on growth and colony forming ability by using uterine sarcoma MES-SA cells. We analyzed the influence of vorinostat on expression of different HDACs, p21(WAF1) and activation of apoptosis. Finally, we examined the antitumor effects of vorinostat on uterine sarcoma in vivo.


RESULTS
Vorinostat efficiently suppressed MES-SA cell growth at a low dosage (3 microM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 microM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours. HDACs class I (HDAC2 and 3) as well as class II (HDAC7) were preferentially affected by this treatment. Vorinostat significantly increased p21(WAF1) expression and apoptosis. Nude mice injected with 5 x 106 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day) and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed. Results obtained by light- and electron-microscopy suggested pronounced activation of apoptosis in tumors isolated from vorinostat-treated mice.


CONCLUSIONS
Our data strongly indicate the high therapeutic potential of vorinostat in uterine sarcomas.
Hrzenjak
Andelko
A
Lore Saldow Research Unit for Molecular Pathology of Gynecologic Tumors, Department of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria. andelko.hrzenjak@medunigraz.at
Moinfar
Farid
F
Kremser
Marie-Luise
ML
Strohmeier
Bettina
B
Petru
Edgar
E
Zatloukal
Kurt
K
Denk
Helmut
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D012509:Sarcoma / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D014410:Tumor Stem Cell Assay; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019394:Ki-67 Antigen; D000077337:Vorinostat; D006655:Histone Deacetylases