Romidepsin (depsipeptide) induced cell cycle arrest, apoptosis and histone hyperacetylation in lung carcinoma cells (A549) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression.
Histone deacetylase inhibitor such as romidepsin (depsipeptide, FR901228, FK228) is a promising new class of antineoplastic agent with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, their precise mechanism of action is uncertain. Histone acetylation and deacetylation are involved in transcriptional activation and transcriptional repression, respectively. Romidepsin induced histone hyperacetylation can be correlated with the cell cycle arrest and apoptosis. In the present study, we investigated the effects of romidepsin on cell proliferation, cell cycle arrest, apoptosis and histone hyperacetylation. Expression of Cdc2/Cdk-1, cyclin B1, cyclin A, p21/Cip1, pRb, pRb2/p130, histone H4 and H3 acetylation status were studied with western blot analysis. The induction of apoptosis has been demonstrated by annexin V-FITC binding assay. Extent of apoptosis has been assessed measuring the activity of caspase-3. Romidepsin led to substantial decrease in the expression of Cdc2/Cdk-1, cyclin B1 and phosphorylated pRb and increase in p21. The pRb protein was found to be one of the targets for the romidepsin induced cell cycle arrest. Flow cytometric analysis showed that romidepsin induced cell cycle arrest at G2-M transition, with significant induction of apoptosis at 25 and 50 nM concentration of romidepsin, with an increase in the number of both early and late apoptotic cells. From this study it is concluded that romidepsin inhibit advanced human lung carcinoma (A549) cell proliferation by altering the expression of cell cycle regulators and apoptotic protein.
Vinodhkumar
Radhakrishnan
R
Department of Biochemistry, University of Madras, Guindy Campus, Chennai-600 025, India.
Song
Young-Sun
YS
Devaki
Thiruvengadam
T
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000235:genetics; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000187:drug effects* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D016160:Retinoblastoma Protein; C087123:romidepsin