title: Sustained inhibition of deacetylases is required for the antitumor activity of the histone deactylase inhibitors panobinostat and vorinostat in models of colorectal cancer.
abstract: Despite compelling preclinical data in colorectal cancer (CRC), the efficacy of HDACIs has been disappointing in the clinic. The goal of this study was to evaluate the effectiveness of vorinostat and panobinostat in a dose- and exposure-dependent manner in order to better understand the dynamics of drug action and antitumor efficacy. In a standard 72 h drug exposure MTS assay, notable concentration-dependent antiproliferative effects were observed in the IC50 range of 1.2-2.8 μmol/L for vorinostat and 5.1-17.5 nmol/L for panobinostat. However, shorter clinically relevant exposures of 3 or 6 h failed to elicit any significant growth inhibition and in most cases a >24 h exposure to vorinostat or panobinostat was required to induce a sigmoidal dose-response. Similar results were observed in colony formation assays where ≥ 24 h of exposure was required to effectively reduce colony formation. Induction of acetyl-H3, acetyl-H4 and p21 by vorinostat were transient and rapidly reversed within 12 h of drug removal. In contrast, panobinostat-induced acetyl-H3, acetyl-H4, and p21 persisted for 48 h after an initial 3 h exposure. Treatment of HCT116 xenografts with panobinostat induced significant increases in acetyl-H3 and downregulation of thymidylate synthase after treatment. Although HDACIs exert both potent growth inhibition and cytotoxic effects when CRC cells were exposed to drug for ≥ 24 h, these cells demonstrate an inherent ability to survive HDACI concentrations and exposure times that exceed those clinically achievable. Continued efforts to develop novel HDACIs with improved pharmacokinetics/phamacodynamics, enhanced intratumoral delivery and class/isoform-specificity are needed to improve the therapeutic potential of HDACIs and HDACI-based combination regimens in solid tumors.
authors.affiliation: Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Wilson
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Labonte
authors.forename: Shelby C
authors.initials: SC
authors.lastname: Martin
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Kuwahara
authors.forename: Anthony
authors.initials: A
authors.lastname: El-Khoueiry
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Robert D
authors.initials: RD
authors.lastname: Ladner
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D000077767:Panobinostat; D013940:Thymidylate Synthase / Q000378:metabolism; D013997:Time Factors; D014410:Tumor Stem Cell Assay; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D009363:Neoplasm Proteins; D000077337:Vorinostat; D000077767:Panobinostat; D013940:Thymidylate Synthase