M344 is a novel synthesized histone deacetylase inhibitor that induces growth inhibition, cell cycle arrest, and apoptosis in human endometrial cancer and ovarian cancer cells.
OBJECTIVE
Histone deacetylase inhibitors (HDACIs) can inhibit cell proliferation, induce cell cycle arrest, and stimulate apoptosis of cancer cells.


METHODS
We investigated the effects of a novel synthesized HDACI, M344, on Ishikawa endometrial cancer cell line, SK-OV-3 ovarian cancer cell line, and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of M344, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated.


RESULTS
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed that all endometrial and ovarian cancer cell lines were sensitive to the growth inhibitory effect of M344, although normal endometrial epithelial cells were viable after the treatment with the same doses of M344 that induced growth inhibition of endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to M344 decreased the proportion of cells in the S-phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Furthermore, M344 treatment of these cell lines increased acetylation of H3 and H4 histone tails.


CONCLUSIONS
These results raise the possibility that M344 may prove particularly effective in the treatment of endometrial cancers and ovarian cancers.
Takai
Noriyuki
N
Department of Obstetrics and Gynecology, Oita University Faculty of Medicine, Hasama-machi, Oita 879-5593, Japan. takai@med.oita-u.ac.jp
Ueda
Tami
T
Nishida
Masakazu
M
Nasu
Kaei
K
Narahara
Hisashi
H
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000077337:Vorinostat
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077337:Vorinostat