Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

Abstract

Artemisinin (ARS) and its derivatives are used for the second-line therapy of malaria infections with Plasmodium falciparum and P. vivax. ARSs also reveal profound antitumor activity in vitro and in vivo. In the present investigation, we correlated the mRNA expression data of 89 angiogenesis-related genes obtained by microarray hybridization from the database of the US National Cancer Institute with the 50% growth inhibition concentration values for eight ARSs (ARS, arteether (ARE), artesunate (ART), artemisetene, arteanuine B, dihydroartemisinylester stereoisomers 1 and 2). The constitutive expression of 30 genes correlated significantly with the cellular response to ARSs. By means of hierarchical cluster analysis and cluster image mapping expression, profiles were identified that determined significantly the cellular response to ART, ARE, artemether and dihydroartemisinylester stereoisomer 1. We have exemplarily validated the microarray data of six out of these 30 genes by realtime RT-PCR in seven cell lines. The fact that sensitivity and resistance of tumor cells could be predicted by the mRNA expression of angiogenesisrelated genes indicate that ARSs reveal their antitumor effects at least in part by inhibition of tumor angiogenesis. As many chemopreventive drugs exert antiangiogenic features, ARSs might also be chemopreventive in addition to their cytotoxic effects.

Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer

“…On the other hand, MMP-9 is highly up-regulated in ovarian cancer, particularly in metastases (19). Our data showed that MMP-9 production was not inhibited by DHA treatment, while Anfosso et al found that artermisinin inhibited the expression of MMP-9 in cancer cells (33). The difference between these findings may be due to different cell lines and/or different treatments.…”

Hypoxia modulates the effect of dihydroartemisinin on endothelial cells

“…In conclusion, considering both data from the literature and the present work, it appears that DHA at 10M or more induces EC and tumor cell death through oxidative stress [18,20,45], which could be caused by DHA directly through the oxidation of reduced flavin cofactors [25]. However, the mechanisms of toxicity of DHA at low doses, especially under hypoxia, needs to be elucidated further.…”

“…In particular, artemisinins reduce EC growth and migration, VEGF and VEGF-receptor expression and new vessel formation in mice bearing Kaposi's sarcoma xenograft tumors [14,[16][17][18][19]. A correlation between genes involved in angiogenesis and the response of tumor cells to artemisinins was demonstrated by transcriptional analysis [20].…”

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

“…Because angiogenesis involves tissue restructuring, genes that regulate angiogenesis, such as chemokine receptors, can also affect tumor metastasis (Wu et al, 2009). In a study conducted with an NCI panel of 60 tumor cell lines, treatment of these cells with ART and related compounds resulted in altered expression of genes implicated in angiogenesis suggesting antiangiogenic activity (Anfosso et al, 2006). In this study, microarray analysis of mRNA expression of 30 out of 89 angiogenesis-related genes correlated significantly with the cellular response to several ARTs.…”

“…The sensitivity and resistance of these tumor cells correlated with the mRNA expression of angiogenesis-related genes. This suggests that that the anti-tumor effects of ARTs are likely due to their role in inhibiting tumor angiogenesis (Anfosso et al, 2006).…”