Artemisinin and Antiangiogenesis activity

by Artemisinin H. Sweat Wormowd, artemisinin research

Artemisinin (ART) is a natural product of the plant sweet wormwood, Artemisia annua L. ARTs are widely known for their potent antimalarial activity, but also been potential anti-cancer activity both in vitro and in vivo over the past few years. ARTs have inhibitory effects on cancer cell growth and also inhibit angiogenesis.

Artemisinin and its derivatives are lactonic sesquiterpenoid compounds first discovered in China. A crude extract of the wormwood plant sweet wormwood, Artemisia annua (qinghao) was first used as an antipyretic 2000 years ago. The antipyretic therapy dates back to the third century B.C. in the “Handbook of Prescriptions for Emergency Treatment” edited by Ge Hong (281-340 B.C.) where he recommended tea-brewed leaves of the wormwood plant to treat fever and chills. The specific effect of ART on the fever of malaria was reported in the 16th century in the “Compendium of Materia Medica” published by Li Shizen in 1596 cited Ge Hong’s prescription (Li and Weina, 2011). The active constituent of the extract was identified and purified in the 1970s, and named qinghaosu, or artemisinin (ART).

Cancer angiogenesis plays a key role in the growth, invasion, and metastasis of cancers. In the process of angiogenesis, the formation of new blood vessels from pre-existing ones is essential for the supply of tumors with oxygen and nutrients. Normal angiogenesis is strictly controlled by some transient, typical physiological processes such as reproduction, development, wound healing; continued angiogenesis is also a characteristic of pathological alteration such as cancer. Cancer is an angiogenesis-dependent disease, and the growth of tumors, intravasation and metastases require angiogenesis. If cancers reach a size for which diffusion alone cannot supply enough oxygen and nutrients, angiogenesis is promoted by numerous pro-angiogenic or anti-angiogenic factors. In human and experimental cancers, new vessels are required for increased delivery of nutrients and are a target for invading tumor cells, and there is a large body of evidence to support a key role for angiogenesis in disease progression. As a consequence, inhibitors of angiogenesis were considered as interesting possibilities for cancer therapy.

After more than 30 years of intensive study, many agents, including novel candidate of Artemisinin, that target angiogenesis as cancer therapy and prevention of metastasis of existing tumors have been translated from the laboratory to the bedside. The anti-angiogenic activities of sweet wormwood Artemisinin were shown using various models of angiogenesis, namely, proliferation, migration and tube formation of endothelial cells. Therefore, sweet wormwood Artemisinin-induced inhibition of angiogenesis could be a promising therapeutic strategy for treatment of cancer and prevention of metastasis.

Angiogenesis process leads to enhanced proliferation of endothelial cells through induction of certain cytokines. Among the cytokines for regulating angiogenesis, VEGF and angiopoietin-1 (Ang-1) have specific modulating effects on the growth of vascular endothelial cells, and they play a key role in the process of angiogenesis. This event occurs via multiple effects including hypoxia-driven activation of expression of HIF-1α and the aryl hydrocarbon receptor nuclear translocator (ARNT). A vital requirement of neovasculogenesis (new formation of blood vessel) is endothelial mitosis, which occurs in response to activation by pro-angiogenic signaling from VEGF and its receptors.

In vitro, VEGF is a potent endothelial cell mitogen. Tumor hypoxia activates the transcription factor hypoxia inducible factor-1α (HIF-1α). This adaptation increases tumor angiogenesis to support the survival of poorly nourished cancer cells. In normal cells, cyclin-dependent kinases (CDK) are the proteins translating signals in order to guide cells through the cell-division cycle. Sweet wormwood Artemisinin have been shown to increase production of reactive oxygen species and also inhibits the hypoxia induced production of a transcription factor, hypoxia inducible factor-1α (HIF1α). The HIF1α transcription factor increases tumor angiogenesis to support the survival of poorly nourished cancer cells.

Sweet wormwood Artemisinin inhibit cell migration and concomitantly decrease the expression of matrix metalloproteinase proteins such as MMP2 and the avß3 integrins in human melanoma cells. Artemisinin also regulates the levels of urokinase plasminogen activator (u-PA), and the matrix metalloproteinases MMP2, MMP7 and MMP9 all of which are related to metastasis.

According to study by Buommino in 2009, Artemisinin-induced cell growth arrest in A375M malignant melanoma tumor cells also affected the viability of A375P cutaneous melanoma tumor cells with both cytotoxic and growth inhibitory effects. In addition, sweet wormwood Artemisinin treatment affected the migratory ability of A375M cells by reducing metalloproteinase 2 (MMP-2) productions and down-regulating αvβ3 integrin expression. These findings support the hypothesis that Artemisinin may serve as a chemotherapeutic agent for melanoma treatment. Furthermore, IL-1beta-induced p38 mitogen-activated protein kinase (MAPK) activation and upregulation of VEGF-C mRNA, and VEGF-C receptor protein levels in LLC cells were also suppressed by Artemisinin or by the p38 MAPK inhibitor SB-203580, suggesting that p38 MAPK could serve as a mediator of proinflammatory cytokine-induced VEGF-C expression. These data support the hypothesis that sweetwormwood Artemisinin may be useful for the prevention of lymph node metastasis by downregulating VEGF-C and reducing tumor lymphangiogenesis.

Study by Wartenberg in 2003 shows that Artemisinin dose dependently inhibited angiogenesis in embryoid bodies and raised the level of intracellular reactive oxygen species. Furthermore impaired organization of the extracellular matrix component laminin and altered expression patterns of matrix metalloproteinases 1, 2, and 9 were observed during the time course of embryoid body differentiation. Consequently accelerated penetration kinetics of the fluorescent anthracycline doxorubicin occurred within the tissue, indicating increased tissue permeability. Artemisinin down-regulated hypoxia-inducible factor-1alpha and vascular endothelial growth factor (VEGF) expression, which control endothelial cell growth. The antiangiogenic effects and the inhibition of hypoxia-inducible factor-1alpha and VEGF were reversed upon cotreatment with the free radical scavengers mannitol and vitamin E, indicating that artemisinin may act via reactive oxygen species generation. Furthermore, capillary formation was restored upon coadministration of exogenous VEGF.

In conclusion, the inhibition of angiogenesis induced by sweet wormwood Artemisinin has been shown to be a mechanism of anti-cancer activity in vitro and in vivo. In particular, cancer angiogenesis plays a key role in the growth, invasion, and metastasis of tumors. Artemisinin-induced inhibition of angiogenesis could be a promising therapeutic strategy for treatment and prevention of cancer.