Vorinostat enhances the activity of temsirolimus in renal cell carcinoma through suppression of survivin levels.
OBJECTIVE
The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has exhibited promising anticancer activity for the treatment of renal cell cancers (RCC). Survivin expression has been implicated in drug resistance and reducing its levels with the histone deacetylase (HDAC) inhibitor vorinostat may enhance the anticancer activity of temsirolimus.


METHODS
The sensitivity of RCC cell lines to the combination of temsirolimus and vorinostat was determined by measuring cell viability, clonogenic survival, and apoptosis. The effects of this combination on survivin levels were determined in vitro and in vivo. Survivin expression was silenced using small interfering RNA to evaluate its role in determining sensitivity to temsirolimus and vorinostat. The effect of the combination on angiogenesis was also determined in RCC xenograft models.


RESULTS
Vorinostat synergistically improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in two xenograft models in vivo. While each single agent led to a modest decrease in survivin levels, the combination dramatically reduced its expression, which correlated with an induction of apoptosis. Silencing survivin levels induced apoptosis and significantly improved the efficacy of temsirolimus and vorinostat. In addition, the temsirolimus/vorinostat combination led to a strong reduction in angiogenesis.


CONCLUSIONS
Vorinostat augmented the anticancer activity of temsirolimus in both in vitro and in vivo models of RCC. The effectiveness of the combination was due to a decrease in survivin levels and corresponding induction of apoptosis, and enhanced inhibition of angiogenesis. Targeting survivin may be a promising therapeutic strategy to improve RCC therapy.
Mahalingam
Devalingam
D
Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, Texas 78245, USA.
Medina
Ernest C
EC
Esquivel
Juan A
JA
Espitia
Claudia M
CM
Smith
Sabrina
S
Oberheu
Kelli
K
Swords
Ronan
R
Kelly
Kevin R
KR
Mita
Monica M
MM
Mita
Alain C
AC
Carew
Jennifer S
JS
Giles
Francis J
FJ
Nawrocki
Steffan T
ST
D020533:Angiogenesis Inhibitors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D007680:Kidney Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077022:Survivin; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; C117749:Birc5 protein, mouse; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin; D000077337:Vorinostat; C401859:temsirolimus; D020123:Sirolimus