Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma.
OBJECTIVE
Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1.


METHODS
Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL.


RESULTS
In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-X(L), and an increase in accumulation of acetylated histone H3, acetylated alpha-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone.


CONCLUSIONS
Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL.
Paoluzzi
Luca
L
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
Scotto
Luigi
L
Marchi
Enrica
E
Zain
Jasmine
J
Seshan
Venkatraman E
VE
O'Connor
Owen A
OA
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D011719:Pyrazines / Q000008:administration & dosage*; D013449:Sulfonamides; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D047630:Depsipeptides; D006877:Hydroxamic Acids; D011719:Pyrazines; D013449:Sulfonamides; D000069286:Bortezomib; C087123:romidepsin; C487081:belinostat