A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer.
Histone deacetylase inhibitors (HDACIs) are a class of antineoplastic agents previously demonstrating preclinical chemosensitizing activity against drug-resistant cancer cells and mouse xenografts. However, whereas clinical studies have shown efficacy against human hematologic malignancies, solid tumor trials have proved disappointing. We previously developed a novel HDACI, "OSU-HDAC42," and herein examine its activity against ovarian cancer cell lines and xenografts. OSU-HDAC42, (i) unlike most HDACIs, elicited a more than five-fold increase in G(2)-phase cells, at 2.5 microM, with G(2) arrest followed by apoptosis; (ii) at 1.0 microM, completely repressed messenger RNA expression of the cell cycle progression gene cdc2; (iii) at low doses (0.25-1.0 microM for 24 hours), induced tumor cell epithelial differentiation, as evidenced by morphology changes and a more than five-fold up-regulation of epithelium-specific cytokeratins; (iv) potently abrogated the growth of numerous ovarian cancer cells, with IC(50) values of 0.5 to 1.0 microM, whereas also remaining eight-fold less toxic (IC(50) of 8.6 microM) to normal ovarian surface epithelial cells; and (v) chemosensitizated platinum-resistant mouse xenografts to cisplatin. Compared with the clinically approved HDACI suberoylanilide hydroxamic acid (vorinostat), 1.0 microM OSU-HDAC42 was more biochemically potent (i.e., enzyme-inhibitory), as suggested by greater gene up-regulation and acetylation of both histone and nonhistone proteins. In p53-dysfunctional cells, however, OSU-HDAC42 was two- to eight-fold less inductive of p53-regulated genes, whereas also having a two-fold higher IC(50) than p53-functional cells, demonstrating some interaction with p53 tumor-suppressive cascades. These findings establish OSU-HDAC42 as a promising therapeutic agent for drug-resistant ovarian cancer and justify its further investigation.
Yang
Ya-Ting
YT
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Balch
Curt
C
Kulp
Samuel K
SK
Mand
Michael R
MR
Nephew
Kenneth P
KP
Chen
Ching-Shih
CS
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D014404:Tubulin; D016203:CDC2 Protein Kinase; D002945:Cisplatin