FR901228, a novel histone deacetylase inhibitor, induces cell cycle arrest and subsequent apoptosis in refractory human pancreatic cancer cells.
Histone deacetylase (HDAC) inhibitors have antiproliferative activity against human cancer cells via cell cycle arrest, differentiation, and apoptosis. However, no report has focused on the apoptotic potential of HDAC inhibitors in refractory human pancreatic cancer. This study was designed to examine the apoptotic potential of FR901228, a novel HDAC inhibitor, in five human pancreatic cancer cell lines: Capan-1, BxPC-3, HPAF, Panc-1, and MIAPaCa-2. FR901228 markedly inhibited the proliferation of all five cell lines (IC50: 1-500 nM), with the greatest effect in MIAPaCa-2 cells. Treatment of each cell line with FR901228 (10-100 nM) caused cell cycle arrest at the G1 or G2/M phase and subsequent apoptosis. FR901228 induced expression of hyperacetylated histone H3 after 3 h of treatment and overexpression of p21Waf-1 after 6 h. In addition, FR901228 induced apoptosis by activating caspase-3, which led to cleavage of p21Waf-1 into a 15-kDa breakdown product and drove cancer cells from cell cycle arrest into apoptosis. FR901228 also decreased the protein level of survivin dramatically. Our results show that FR901228 markedly inhibits the growth of pancreatic cancer cells, not only through cell cycle arrest, but also through subsequent apoptosis; this was accompanied by caspase-3 activation, survivin degradation, and p21Waf-1 cleavage. FR901228 may prove clinically useful as an agent for refractory pancreatic cancers.
Sato
Nariatsu
N
Department of Surgical Oncology, Graduate School of Medicine, Kanazawa University, Kanazawa 920-0934, Japan.
Ohta
Tetsuo
T
Kitagawa
Hirohisa
H
Kayahara
Masato
M
Ninomiya
Itasu
I
Fushida
Sachio
S
Fujimura
Takashi
T
Nishimura
Gen-Ichi
G
Shimizu
Koichi
K
Miwa
Koichi
K
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D053938:DNA Fragmentation; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D020128:Inhibitory Concentration 50; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000378:metabolism; D009363:Neoplasm Proteins; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D011419:Propidium / Q000494:pharmacology; D000077022:Survivin; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D004396:Coloring Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010456:Peptides, Cyclic; D010718:Phosphatidylserines; D000077022:Survivin; D013778:Tetrazolium Salts; D013844:Thiazoles; D011419:Propidium; C087123:romidepsin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C022616:thiazolyl blue