Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma.
BACKGROUND
Vorinostat (suberoylanilide hydroxamic acid, SAHA), an inhibitor of class I and II histone deacetylases, has been approved for the treatment of cutaneous T-cell lymphoma. In spite of emerging information on the effect of vorinostat in many types of cancer, little is yet known about this drug's mechanism of action, which is essential for its proper use in combination therapy. We investigated alterations in gene expression profile over time in cutaneous T-cell lymphoma cells treated with vorinostat. Subsequently, we evaluated inhibitors of PI3K, PIM and HSP90 as potential combination agents in the treatment of cutaneous T-cell lymphoma.


METHODS
The genes significantly up- or down-regulated by vorinostat over different time periods (2-fold change, false discovery rate corrected P value<0.05) were selected using the short-time series expression miner. Cell viability was assessed in vitro in cutaneous T-cell lymphoma cells through measuring intracellular ATP content. Drug interactions were analyzed by the combination index method with CalcuSyn software.


RESULTS
The functional analysis suggests that vorinostat modifies signaling of T-cell receptor, MAPK, and JAK-STAT pathways. The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that vorinostat inhibits phosphorylation of these kinases. With regards to effects on cutaneous T-cell lymphoma cells, combining vorinostat with PI3K inhibitors resulted in synergy while cytotoxic antagonism was observed when vorinostat was combined with HSP90 inhibitor.


CONCLUSIONS
These results demonstrate the potential targets of vorinostat, underlining the importance of T-cell receptor signaling inhibition following vorinostat treatment. Additionally, we showed that combination therapies involving histone deacetylase inhibitors and inhibitors of PI3K are potentially efficacious for the treatment of cutaneous T-cell lymphoma.
Wozniak
Magdalena B
MB
Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
Villuendas
Raquel
R
Bischoff
James R
JR
Aparicio
Carmen Blanco
CB
Martínez Leal
Juan F
JF
de La Cueva
Paloma
P
Rodriguez
Ma Elena
ME
Herreros
Beatriz
B
Martin-Perez
Daniel
D
Longo
Maria I
MI
Herrera
Marta
M
Piris
Miguel A
MA
Ortiz-Romero
Pablo L
PL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; D006877:Hydroxamic Acids; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D000077337:Vorinostat; D000255:Adenosine Triphosphate; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D006655:Histone Deacetylases