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Sinomenine hydrochloride inhibits human hepatocellular carcinoma cell growth in vitro and in vivo: involvement of cell cycle arrest and apoptosis induction.
- Source :
-
International journal of oncology [Int J Oncol] 2013 Jan; Vol. 42 (1), pp. 229-38. Date of Electronic Publication: 2012 Nov 16. - Publication Year :
- 2013
-
Abstract
- Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, therapies against HCC to date have not been completely effective. Sinomenine hydrochloride (SH), an anti‑arthritis drug applied in clinical practice, has been reported to have in vitro anti‑neoplastic activity in various cancer cells. Whether SH inhibits HCC remains unknown. For this purpose, in this study, MTT assay was used to determine cell growth. Flow cytometry, Hoechst staining, DNA fragmentation, western blot analysis, immunohistochemisty and TUNEL staining were performed to investigate the mechanisms involved. The in vivo activity of SH was determined using a mouse xenograft model. SH inhibited the growth of various types of human HCC cells in vitro. We found that SH promoted cell cycle arrest in the G1 phase and sub‑G1 formation, associated with the increased p21/WAF1/Cip1 expression. Additionally, SH induced caspase‑dependent apoptosis, which involved the disruption of mitochondrial membrane potential, the increased release of cytochrome c and Omi/HtrA2 from the mitochondria into the cytoplasm, the downregulation of Bcl‑2 and the upregulation of Bax, the activation of a caspase cascade (caspase‑8, -10, -9 and -3) and PARP, as well as the decreased expression of survivin. The SH‑suppressed growth of human HCC xenografts in vivo occurred due to the decrease in proliferation and the induction of apoptosis, implicating the activation of caspase‑3, the upregulation of p21 and the downregulation of survivin. These findings suggest that SH exhibits anticancer efficacy in vitro and in vivo involving cell cycle and caspase‑dependent apoptosis and may serve as a potential drug candidate against HCC.
- Subjects :
- Animals
Blotting, Western
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular metabolism
Caspases metabolism
Cyclin-Dependent Kinase Inhibitor p21 metabolism
Cytochromes c metabolism
Flow Cytometry
Humans
In Vitro Techniques
Liver Neoplasms drug therapy
Liver Neoplasms metabolism
Male
Membrane Potential, Mitochondrial drug effects
Mice
Mice, Inbred BALB C
Mice, Nude
Poly(ADP-ribose) Polymerases metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Tumor Cells, Cultured
bcl-2-Associated X Protein metabolism
Apoptosis drug effects
Carcinoma, Hepatocellular pathology
Cell Cycle Checkpoints drug effects
Cell Proliferation drug effects
Liver Neoplasms pathology
Morphinans pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2423
- Volume :
- 42
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- International journal of oncology
- Publication Type :
- Academic Journal
- Accession number :
- 23165705
- Full Text :
- https://doi.org/10.3892/ijo.2012.1704