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 G(2) 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.
National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Jung-Hyun
JH
Park
Yeonjoo
Y
Jung
Tai Young
TY
Kim
Sang Gyun
SG
Kim
Hyun-Soon
HS
Jong
Jung Weon
JW
Lee
Dae-Kee
DK
Kim
Jong-Soo
JS
Lee
Noe Kyeong
NK
Kim
Tae-You
TY
Kim
Yung-Jue
YJ
Bang
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D013274:Stomach Neoplasms / Q000188:drug therapy; D013997:Time Factors
D000577:Amides; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011759:Pyrrolidines; D012097:Repressor Proteins; C497103:SK-7041; C497104:SK-7068; D004247:DNA; C110550:HDAC1 protein, human; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2