Brazilian Propolis Suppresses Tumor Growth

Brazilian Propolis Suppresses Angiogenesis by Inducing Apoptosis in Tube-forming Endothelial Cells through Inactivation of Survival Signal ERK1/2
Evidence-based Compl. and Alt. Medicine, Published online on April 7, 2009

We recently reported that propolis suppresses tumor-induced angiogenesis through tube formation inhibition and apoptosis induction in endothelial cells. However, molecular mechanisms underlying such angiogenesis suppression by propolis have not been fully elucidated.

The aim of this study was to investigate the effects of ethanol extract of Brazilian propolis (EEBP) on two major survival signals, extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt, and to elucidate whether changes in these signals were actually involved in antiangiogenic effects of the propolis. Detection by western blotting revealed that EEBP suppressed phosphorylation of ERK1/2, but not that of Akt. Pharmacological inhibition by U0126 demonstrated that ERK1/2 inactivation alone was enough to inhibit tube formation and induce apoptosis. It was also shown that EEBP and U0126 similarly induced activation of caspase-3 and cleavage of poly ADP-ribose polymerase (PARP) and lamin A/C, all of which are molecular markers of apoptosis.

These results indicate that inhibition of survival signal ERK1/2, and subsequent induction of apoptosis, is a critical mechanism of angiogenesis suppression by EEBP…

Propolis is generally used as an alcohol or water extracts in human applications and not as a single purified compound. In addition, the chemical composition of propolis is known to vary qualitatively and quantitatively depending upon their geographical and botanical origins (23,32). Due to such differences, biological activities of propolis also differ depending upon their origins (23,33–35). Hence, it is very important to evaluate biological activities of propolis in extracted form with specified geographical and botanical origins and clarified chemical composition (36).

In this study, we showed that EEBP inhibited ERK1/2 activation. We previously reported that Brazilian propolis, collected from Baccharis dracunculifolia DC. in Minas Gerais State, were composed mainly of artepillin C, caffeic acid and p-coumaric acid (23,37). We also reported recently that several constituents of Brazilian and Uruguayan propolis possessed antiangiogenic activities with varying degrees (38). We would like to further investigate which constituents of the propolis are responsible for ERK1/2 inactivation in endothelial cells. Although EEBP and U0126 had very similar effects on tube formation inhibition and apoptosis induction, it should be noted that the propolis exhibited stronger antiangiogenic activities, such as inhibiting elongation of endothelial cells during tube formation, than those of U0126. Such results suggest a possibility that there might be mechanism(s) other than ERK1/2 inactivation in angiogenesis suppression by EEBP. We would like to further investigate how the propolis affects other signaling pathways involved in angiogenesis and apoptosis. We hope our findings on antiangiogenic effects of propolis will help us improve medical treatment and prevention of human cancer and other angiogenesis-related diseases.