Abstract |
Although arsenic trioxide ( As2O3) has been successfully employed in treatment of patients with APL ( acute promyelocytic leukemia), the sensitivity of solid tumor cells to this treatment was much lower than APL cells. The single agent of As2O3 was inefficient for treatment of hepatocellular carcinoma (HCC) in phase II trial demonstrating that new modalities of treatment with enhanced therapeutic effect are needed. In this study, we showed that oridonin, a diterpenoid isolated from traditional Chinese medicine Rabdosia rubescences, greatly potentiated apoptosis induced by As2O3 in hepatocellular carcinoma cells. The synergistic pro-apoptosis effect of combination of these two drugs led to increase in intracellular reactive oxygen species (ROS) level and N-acetyl-L-cysteine (NAC), a thiol-containing anti-oxidant, was able to completely block the effect. The combination treatment induced ROS-dependent decrease in mitochondrial membrane potential ( MMP) decrease, and relocation of Bax and cytochrome C. Besides, oridonin dramatically increased the intracellular Ca2+ overload triggered by As2O3. Furthermore, the co-treatment of oridonin and As2O3 induced ROS-mediated down-regulation of Akt and XIAP, and inhibition of NF-κB activation. The two drug combination enhanced tumor suppression activity in murine HCC model compared with single agent treatment in vivo. These findings demonstrate that oridonin can sensitize hepatocellular carcinoma cells to As2O3 treatment and will facilitate the optimization of As2O3 therapy for HCC patients.
|
Authors | Guo Chen, Ke Wang, Bing-Ya Yang, Bo Tang, Jian-Xiang Chen, Zi-Chun Hua |
Journal | International journal of oncology
(Int J Oncol)
Vol. 40
Issue 1
Pg. 139-47
(Jan 2012)
ISSN: 1791-2423 [Electronic] Greece |
PMID | 21947421
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Arsenicals
- Diterpenes, Kaurane
- NF-kappa B
- Oxides
- Reactive Oxygen Species
- X-Linked Inhibitor of Apoptosis Protein
- oridonin
- Proto-Oncogene Proteins c-akt
- Mitogen-Activated Protein Kinases
- Arsenic Trioxide
|
Topics |
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Arsenic Trioxide
- Arsenicals
(administration & dosage, pharmacology)
- Carcinoma, Hepatocellular
(drug therapy, metabolism)
- Cell Line, Tumor
- Diterpenes, Kaurane
(administration & dosage, pharmacology)
- Drug Synergism
- Female
- Humans
- Liver Neoplasms
(drug therapy, metabolism)
- Liver Neoplasms, Experimental
(drug therapy, metabolism)
- Membrane Potential, Mitochondrial
(drug effects)
- Mice
- Mice, Inbred C57BL
- Mitogen-Activated Protein Kinases
(metabolism)
- NF-kappa B
(antagonists & inhibitors, metabolism)
- Neoplasm Transplantation
- Oxides
(administration & dosage, pharmacology)
- Proto-Oncogene Proteins c-akt
(antagonists & inhibitors, metabolism)
- Reactive Oxygen Species
(metabolism)
- X-Linked Inhibitor of Apoptosis Protein
(antagonists & inhibitors, metabolism)
|