Ricolinostat, a selective HDAC6 inhibitor, shows anti-lymphoma cell activity alone and in combination with bendamustine.
Histone deacetylase inhibitors (HDACis) have emerged as a new class of anticancer agents, targeting the biological process including cell cycle and apoptosis. We investigated and explained the anticancer effects of an HDAC6 inhibitor, ricolinostat alone and in combination with bendamustine in lymphoma cell lines. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) generation, Bcl-2 protein expression, cell cycle progression and tubuline expression were determined by flow cytometry. The effects of ricolinostat alone and in combination on the caspases, PI3K/Akt, Bcl-2 pathways, ER stress and UPR were assessed by immunoblotting. Ricolinostat shows anti lymphoma activity when used as single agent and its capability to induce apoptosis is synergistically potentiated by the bendamustine in lymphoma cell lines. Drug combination reduced the proportion of cells in the G0/G1and S phases and caused an increase of "sub-G0/G1" peak. The synergistic effect accompanied with the increased ROS, activation of caspase-8, -9, and -3, the cleavage of PARP and modulated by Bcl-2 proteins family. In addition, the exposure of ricolinostat induced the acetylation level of α-tubulin, the extend of which was not further modified by bendamustine. Finally, the apoptosis effect of ricolinostat/bendamustine may be mediated by a corresponding effect on microtubule stabilization. Our data suggest that ricolinostat in combination with bendamustine may be a novel combination with potential for use as an antitumor agent in lymphoma.
Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41124, Modena, Italy.
Maria
M
Cosenza
Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41124, Modena, Italy.
Monica
M
Civallero
Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41124, Modena, Italy.
Luigi
L
Marcheselli
Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41124, Modena, Italy.
Stefano
S
Sacchi
Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41124, Modena, Italy. samantha.pozzi@unimore.it.
Samantha
S
Pozzi
D000107:Acetylation / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000069461:Bendamustine Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
C000595707:BCL2 protein, human; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D014404:Tubulin; D016753:Interleukin-10; D000069461:Bendamustine Hydrochloride; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; C572255:ricolinostat
Apoptosis; Bendamustine; Lymphoma; Ricolinostat; Synergistic effect