Class I Histone Deacetylase-Selective Novel Synthetic Inhibitors Potently Inhibit Human Tumor Proliferation

We have developed previously a class of synthetic hybrid histone deacetylase (HDAC) inhibitors, which were built from hydroxamic acid of trichostatin A and pyridyl ring of MS-275. In this study we evaluated the antitumor effects of these novel hybrid synthetic HDAC inhibitors, SK-7041 and SK-7068, on human cancer cells. Both SK-7041 and SK-7068 effectively inhibited cellular HDAC activity at nanomolar concentrations and induced the time-dependent hyperacetylation of histones H3 and H4. These HDAC inhibitors preferentially inhibited the enzymatic activities of HDAC1 and HDAC2, as compared with the other HDAC isotypes, indicating that class I HDAC is the major target of SK-7041 and SK-7068. We found that these compounds exhibited potent antiproliferative activity against various human cancer cells in vitro. Growth inhibition effect of SK-7041 and SK-7068 was related with the induction of aberrant mitosis and apoptosis in human gastric cancer cells. Both compounds induced the accumulation of cells at mitosis after 6 h of treatment, which was demonstrated by accumulation of tetraploid cells, lack of G2 cyclin/cyclin-dependent kinase inactivation, and higher mitotic index. After 12 h of treatment, apoptotic cells were increased through mitochondrial and caspase-mediated pathway. Finally, in vivo experiment showed that SK-7041 or SK-7068 was found to reduce the growth of implanted human tumors in nude mice. Therefore, based on isotype specificity and antitumor activity, SK-7041 and SK-7068 HDAC inhibitors are expected to be promising anticancer therapeutic agents and need additional clinical development.

[1]  J. Y. Lee,et al.  Synthesis and biological evaluation of 3-(4-substituted-phenyl)-N-hydroxy-2-propenamides, a new class of histone deacetylase inhibitors. , 2003, Journal of medicinal chemistry.

[2]  Ricky W Johnstone,et al.  Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? , 2003, Cancer cell.

[3]  So-jung Kim,et al.  Inhibition of histone deacetylase activity increases chromosomal instability by the aberrant regulation of mitotic checkpoint activation , 2003, Oncogene.

[4]  Minoru Yoshida,et al.  FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. , 2002, Cancer research.

[5]  T. Fojo,et al.  Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity. , 2002, Molecular cancer therapeutics.

[6]  A. Kalita,et al.  Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors. , 2002, Cancer research.

[7]  Manfred Jung,et al.  Structure-activity relationships on phenylalanine-containing inhibitors of histone deacetylase: in vitro enzyme inhibition, induction of differentiation, and inhibition of proliferation in Friend leukemic cells. , 2002, Journal of medicinal chemistry.

[8]  Xiao-Fan Wang,et al.  HDAC6 is a microtubule-associated deacetylase , 2002, Nature.

[9]  Ricky W. Johnstone,et al.  Histone-deacetylase inhibitors: novel drugs for the treatment of cancer , 2002, Nature Reviews Drug Discovery.

[10]  Robert Brown,et al.  Epigenomics and epigenetic therapy of cancer. , 2002, Trends in molecular medicine.

[11]  Ping Zhu,et al.  Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells , 2001, The EMBO journal.

[12]  N. Rosen,et al.  The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. , 2001, Cancer research.

[13]  P. Marks,et al.  Histone deacetylases and cancer: causes and therapies , 2001, Nature Reviews Cancer.

[14]  R. Dahiya,et al.  Histone deacetylase and DNA methyltransferase in human prostate cancer. , 2001, Biochemical and biophysical research communications.

[15]  T. Heinzel,et al.  Histone deacetylase as a therapeutic target , 2001, Trends in Endocrinology & Metabolism.

[16]  R. Momparler,et al.  Antineoplastic action of 5-aza-2′-deoxycytidine and histone deacetylase inhibitor and their effect on the expression of retinoic acid receptor β and estrogen receptor α genes in breast carcinoma cells , 2001, Cancer Chemotherapy and Pharmacology.

[17]  M. Nishiyama,et al.  Histone deacetylase as a new target for cancer chemotherapy , 2001, Cancer Chemotherapy and Pharmacology.

[18]  P. Pandolfi Histone deacetylases and transcriptional therapy with their inhibitors , 2001, Cancer Chemotherapy and Pharmacology.

[19]  N. Ahn,et al.  Mitotic phosphorylation of Golgi reassembly stacking protein 55 by mitogen-activated protein kinase ERK2. , 2001, Molecular biology of the cell.

[20]  T. Tsuruo,et al.  Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. , 2001, Cancer research.

[21]  C. Cordon-Cardo,et al.  Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  Sang Gyun Kim,et al.  Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-β1-induced apoptosis in human gastric cancer cells , 2001, Oncogene.

[23]  G. Otterson,et al.  DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. , 2001, Cancer research.

[24]  E. Sausville,et al.  MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells. , 2001, Cancer research.

[25]  M. Yoshida,et al.  Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[26]  A. Escargueil,et al.  Mitotic Phosphorylation of DNA Topoisomerase II α by Protein Kinase CK2 Creates the MPM-2 Phosphoepitope on Ser-1469* , 2000, The Journal of Biological Chemistry.

[27]  H. W. Lee,et al.  Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. , 2000, Cancer research.

[28]  D. Fairlie,et al.  Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. , 2000, Molecular biology of the cell.

[29]  D. Cohen,et al.  Histone Deacetylase Inhibition Selectively Alters the Activity and Expression of Cell Cycle Proteins Leading to Specific Chromatin Acetylation and Antiproliferative Effects* , 1999, The Journal of Biological Chemistry.

[30]  T. Suzuki,et al.  Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. , 1999, Journal of medicinal chemistry.

[31]  T. Tsuruo,et al.  A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  L. Wu,et al.  MPM-2 antibody-reactive phosphorylations can be created in detergent-extracted cells by kinetochore-bound and soluble kinases. , 1997, Journal of cell science.

[33]  Bruce M. Spiegelman,et al.  Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein , 1996, Science.

[34]  A. Kumagai,et al.  Purification and Molecular Cloning of Plx1, a Cdc25-Regulatory Kinase from Xenopus Egg Extracts , 1996, Science.

[35]  L. Gerace,et al.  Cloning of cDNAs for M-phase phosphoproteins recognized by the MPM2 monoclonal antibody and determination of the phosphorylated epitope. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D A Scudiero,et al.  Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. , 1988, Cancer research.

[37]  F. M. Davis,et al.  Monoclonal antibodies to mitotic cells. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Herman,et al.  Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer , 1999, Nature Genetics.