The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors Yu-Ling Lin,1,2 Wen-Lin Lai,3,4 Horng-jyh Harn,5 Pei-Hsiu Hung,6,7 Ming-Chang Hsieh,4 Kai-Fu Chang,3 Xiao-Fan Huang,3 Kuang-Wen Liao,1,8 Ming-Shih Lee,3,4 and Nu-Man Tsai3,4
1College of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan 2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu 30010, Taiwan 3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan 4Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan 5Department of Pathology, China Medical University Hospital, Taichung 40402, Taiwan 6Department of Traditional Chinese Medicin, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan 7Department of Bioindustry Technology, Da-Yeh University, Changhua 51591, Taiwan 8Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu 30010, Taiwan
Abstract Glioblastoma multiforme (GBM) is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer.
A novel polysaccharide, isolated from Angelica
sinensis (Oliv.) Diels induces the apoptosis of cervical cancer HeLa
cells through an intrinsic apoptotic pathway.
Cao W, Li XQ, Wang X, Fan HT, Zhang XN, Hou Y, Liu SB, Mei QB. Department
of Pharmacology, School of Pharmacy, the Fourth Military Medical
University, 169 West Changle Road, Xi'an, Shaanxi 710032, China.
A novel polysaccharide isolated from Angelica sinensis, named
APS-1d showed cytotoxic activity towards several cancer cell lines in
vitro. However, the precise antitumor mechanisms of this compound are
unknown. In this study, we investigated the pro-apoptotic effects of
APS-1d in human cervical cancer HeLa cells both in vitro and in vivo,
and further elucidated the mechanisms of this action. Inhibition of HeLa
cell proliferation was determined by MTT assay and the therapeutic
efficacy of APS-1d was evaluated by human cancer xenografts in nude
mice. Cell apoptosis was examined with flow cytometry and TUNEL assay.
The mechanism of action of APS-1d was investigated by Western blot
analysis. APS-1d decreased HeLa cell proliferation in a concentration-
and time-dependent manner in vitro. In addition, APS-1d significantly
inhibited tumor growth in athymic nude mice. Characteristic
manifestations of apoptosis including apoptotic morphological features
and the sub- [G.sub.0]/[G.sub.1] peaks were observed when the cells were
treated with APS-1d. Further analysis showed that APS-1d-induced
apoptosis was associated with the regulation of Bcl-2 family protein
expression, a decrease in the mitochondrial membrane potential, and an
increase in the cytosolic cytochrome c levels. Sequentially, APS-1d
increased the activities of caspase-9, -3, and poly (ADP-ribose)
polymerase in a concentration-dependent manner, however, no obvious
activation of Bid and caspase-8 was observed. Pretreatment with
Z-LEHD-FMK, a specific inhibitor of caspase-9, significantly attenuated
APS-1d-induced cell apoptosis, and activation of caspase-3. Taken
together, our studies indicate that APS-1d is capable of inhibiting HeLa
cell proliferation and inducing apoptosis in these cells which primarily
involves the activation of the intrinsic mitochondrial pathway.
The Antitumor Effects of Angelica sinensis on Malignant Brain Tumors In vitro and In vivo
Wen-Liang Chang5 and
Abstract Purpose: In this study, we have examined the antitumor effects of chloroform extract of Angelica sinensis (AS-C), a traditional Chinese medicine, on glioblastoma multiforme (GBM) brain tumors in vitro and in vivo.
Experimental Design:In vitro, GBM cells were treated with AS-C, and the cell proliferation, changes in distributions of cell cycle, and apoptosis were determined. In vivo, human DBTRG-05MG and rat RG2 GBM tumor cells were injected s.c. or i.c. and were treated with AS-C. Effects on tumor growth were determined by tumor volume, magnetic resonance imaging, survival, and histology analysis.
Results: The AS-C displays potency in suppressing growth of malignant brain tumor cells without cytotoxicity to fibroblasts. Growth suppression of malignant brain tumor cells by AS-C results from cell cycle arrest and apoptosis. AS-C can up-regulate expression of cdk inhibitors, including p21, to decrease phosphorylation of Rb proteins resulting in cell arrest at the G0-G1 phase for DBTRG-05MG and RG2 cells. The apoptosis-associated proteins are dramatically increased and activated in DBTRG-05MG cells and RG2 cells by AS-C but RG2 cells without p53 protein expression. In vitro results showed AS-C triggered both p53-dependent and p53-independent pathways for apoptosis. In in vivo studies, AS-C not only can suppress growths of malignant brain tumors of rat and human origin but also shrink the volumes of in situ GBM, significantly prolonging survivals.
Conclusions: The in vitro and in vivo anticancer effects of AS-C indicate that it has sufficient potential to warrant further investigation and development as a new anti–brain tumor agent.