title: Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma.
abstract: Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, cell-type specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.
authors: a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.|b Cancer Biology Program , University of Arizona , Tucson , AZ , USA.
authors: Aaron P
authors: AP
authors: Havas
authors: a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.
authors: Kameron B
authors: KB
authors: Rodrigues
authors: a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.
authors: Anvi
authors: A
authors: Bhakta
authors: a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.
authors: Joseph A
authors: JA
authors: Demirjian
authors: c Department of Pediatrics, Steele Children's Research Center, College of Medicine , University of Arizona , Tucson , AZ , USA.
authors: Seongmin
authors: S
authors: Hahn
authors: d Department of Pathology, College of Medicine , University of Arizona , Tucson , AZ , USA.
authors: Jack
authors: J
authors: Tran
authors: a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.|e Biological Chemistry Program , College of Medicine, University of Arizona , Tucson , AZ , USA.
authors: Margarethakay
authors: M
authors: Scavello
authors: a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.
authors: Ana A
authors: AA
authors: Tula-Sanchez
authors: c Department of Pediatrics, Steele Children's Research Center, College of Medicine , University of Arizona , Tucson , AZ , USA.
authors: Yi
authors: Y
authors: Zeng
authors: e Biological Chemistry Program , College of Medicine, University of Arizona , Tucson , AZ , USA.
authors: Monika
authors: M
authors: Schmelz
authors: a Department of Pharmacology and Toxicology , College of Pharmacy, University of Arizona , Tucson , AZ , USA.|b Cancer Biology Program , University of Arizona , Tucson , AZ , USA.|e Biological Chemistry Program , College of Medicine, University of Arizona , Tucson , AZ , USA.
authors: Catharine L
authors: CL
authors: Smith
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008938:Mitosis / Q000187:drug effects*; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology; D011123:Polyploidy; D013449:Sulfonamides / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D015854:Up-Regulation; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D003603:Cytotoxins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D050257:Tubulin Modulators; D014750:Vincristine; C487081:belinostat; D017239:Paclitaxel
keywords: Cell cycle; drug resistance; histone deacetylase inhibitor; lymphoma; microtubule; mitosis; polyploidy