title: Combination of HDAC and topoisomerase inhibitors in small cell lung cancer.
abstract: Histone deacetylase (HDAC) inhibitors, including MGCD0103 and vorinostat, have led to tumor growth inhibition and apoptosis in vivo. However, with limited single-agent activity demonstrated in solid tumor trials, we examined the potential for enhanced effects in combination with topoisomerase I and II inhibitors, a staple for treatment in refractory small cell lung cancer (SCLC). SCLC cell lines were exposed to increasing concentrations of single-agent HDAC inhibitors and topoisomerase inhibitors, in various combinations, to assess for cell viability, additivity or synergy, and apoptosis. We found that MGCD0103 and vorinostat decreased cell viability by at least 60% and 80%, respectively. In the majority of cell lines, the strongest synergism was seen when vorinostat was followed by either etoposide or topotecan; concurrent therapy led to antagonism in most cell lines. Synergistic effects were seen when MGCD0103 was given concurrently or sequentially with both amrubicin and epirubicin. Enhanced additive effects leading to caspase activation were noted for the combination of MGCD0103 or vorinostat with a topoisomerase inhibitor vs. either agent alone. Thus, the combination of HDAC inhibitors and topoisomerase inhibitors showed enhanced cytotoxic effects in SCLC cell lines. Further evaluation in a clinical setting may be warranted.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Jhanelle
authors.initials: J
authors.lastname: Gray
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cubitt
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiappori
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology / Q000633:toxicity; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000633:toxicity; D055752:Small Cell Lung Carcinoma / Q000378:metabolism*; D059003:Topoisomerase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000077337:Vorinostat
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011743:Pyrimidines; D059003:Topoisomerase Inhibitors; D000077337:Vorinostat; C523184:mocetinostat; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3