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Millepachine, a novel chalcone, induces G 2 /M arrest by inhibiting CDK1 activity and causing apoptosis via ROS-mitochondrial apoptotic pathway in human hepatocarcinoma cells in vitro and in vivo
- Source :
- Carcinogenesis. 34:1636-1643
- Publication Year :
- 2013
- Publisher :
- Oxford University Press (OUP), 2013.
-
Abstract
- In this study, we reported millepachine (MIL), a novel chalcone compound for the first time isolated from Millettia pachycarpa Benth (Leguminosae), induced cell cycle arrest and apoptosis in human hepatocarcinoma cells in vitro and in vivo. In in vitro screening experiments, MIL showed strong antiproliferation activity in several human cancer cell lines, especially in HepG2 cells with an IC50 of 1.51 µM. Therefore, we chose HepG2 and SK-HEP-1 cells to study MIL's antitumor mechanism. Flow cytometry showed that MIL induced a G2/M arrest and apoptosis in a dose-dependent manner. Western blot demonstrated that MIL-induced G2/M arrest was correlated with the inhibition of cyclin-dependent kinase 1 activity, including a remarkable decrease in cell division cycle (cdc) 2 synthesis, the accumulation of phosphorylated-Thr14 and decrease of phosphorylation at Thr161 of cdc2. This effect was associated with the downregulation of cdc25C and upmodulation of checkpoint kinase 2 in response to DNA damage. MIL also activated caspase 9 and caspase 3, and significantly increased the ratio of Bax/Bcl-2 and stimulated the release of cytochrome c into cytosol, suggesting MIL induced apoptosis via mitochondrial apoptotic pathway. Associated with those effects, MIL also induced the generation of reactive oxygen species. In HepG2 tumor-bearing mice models, MIL remarkably and dose dependently inhibited tumor growth. Treatment of mice with MIL (20mg/kg intravenous [i.v.]) caused more than 65% tumor inhibition without cardiac damage compared with 47.57% tumor reduction by 5mg/kg i.v. doxorubicin with significant cardiac damage. These effects suggested that MIL and its easily modified structural derivative might be a potential lead compound for antitumor drug.
- Subjects :
- Cancer Research
Carcinoma, Hepatocellular
Cell cycle checkpoint
DNA damage
Mice, Nude
Apoptosis
Caspase 3
Cyclin B
Millettia
Membrane Potentials
Inhibitory Concentration 50
Mice
Chalcone
Chalcones
Cytosol
Cyclin-dependent kinase
CDC2 Protein Kinase
Animals
Humans
Phosphorylation
Mice, Inbred BALB C
Cyclin-dependent kinase 1
Dose-Response Relationship, Drug
biology
Chemistry
Cytochrome c
Liver Neoplasms
Hep G2 Cells
General Medicine
Cell cycle
Flow Cytometry
Antineoplastic Agents, Phytogenic
Xenograft Model Antitumor Assays
Molecular biology
Cyclin-Dependent Kinases
Mitochondria
Enzyme Activation
G2 Phase Cell Cycle Checkpoints
biology.protein
Female
Reactive Oxygen Species
DNA Damage
Subjects
Details
- ISSN :
- 14602180 and 01433334
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Carcinogenesis
- Accession number :
- edsair.doi.dedup.....affe8574b010ec5e619115d586878091