The Apoptotic Effect of D Rhamnose β-Hederin, a Novel Oleanane-Type Triterpenoid Saponin on Breast Cancer Cells

Abstract

There is growing interest in development of natural products as anti-cancer and chemopreventive agents. Many triterpenoids have been proved as potential agents for chemoprevention and therapy of breast cancer. Ginsenosides from ginseng, which mostly belong to dammarane-type triterpenoids, have gained great attention for their anti-breast cancer activity with diverse mechanisms. However, studies of other kinds of triterpenoid saponins on breast cancer are limited. Previously, we purified and identified a novel oleanane-type triterpene saponin named D Rhamnose β-hederin (DRβ-H) from Clematis ganpiniana, a Chinese traditional anti-tumor herb. In the present study, DRβ-H showed strong inhibitory activity on the growth of various breast cancer cells and induced apoptosis in these cells. DRβ-H inhibited PI3K/AKT and activated ERK signaling pathway. PI3K inhibitor LY294002 synergistically enhanced DRβ-H-induced apoptosis whereas MEK inhibitor U0126 reduced the apoptosis rate. Moreover, DRβ-H regulated the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family proteins. Furthermore, DRβ-H induced depolarization of mitochondrial membrane potential which released Apaf-1 and Cytochrome C from the inter membrane space into the cytosol, where they promoted caspase-9 and caspase-3 activation. This is the first report on the pro-apoptotic effects of DRβ-H, a novel oleanane-type triterpenoid saponin, on breast cancer cells and its comprehensive apoptosis pathways. It implied that oleanane-type triterpenoid saponin DRβ-H could be a promising candidate for chemotherapy of breast cancer.

D Rhamnose β‑Hederin against human breast cancer by reducing tumor‑derived exosomes

“…This was based on MTT assay results and confirmed with flow cytometry analysis of cancer cells incubated with different concentrations of DRβ-H. It was previously reported that DRβ-H regulated the phosphoinositide 3-kinase/AKT serine threonine kinase signaling pathway and activated pro-apoptotic proteins of the B cell lymphoma-2 family ( 5 ). No apoptosis-associated signaling pathways were examined in the present study, and it will be necessary to investigate the concrete pathways involved in proliferation inhibition.…”

“…A large number of active components purified from natural plants have been used to treatvarious tumors including breast cancer ( 2 , 3 ). The authors' previous study demonstrated that DRβ-H, a noveloleanane-type triterpenoid saponin derived from Clematis ganpiniana , exhibited apotentinhibitory effecton breastcancer cells ( 5 ). In the present study, it was reported that DRβ-H may inhibit breast cancer cell growth by remodeling the tumor microenvironment via reducing exosome release.…”

“…The inhibitory effect of DRβ-H on breast cancer cells was determined usingan MTT assay as previously described with minor modifications ( 5 ). Briefly, 5×10 3 cells were cultured in 96-well plates in triplicate.…”

“…Furthermore, D Rhamnose β-hederin (3β-[(α-L-arabinopyranosyl)-oxy] olean-12-en-28-oicacid) (DRβ-H), one of the isolated oleanane-type triterpenoid saponins, was investigated. The apoptotic activity and anticancer properties of DRβ-H have been previously demonstrated, suggesting that DRβ-H may be a potential treatment for breast cancer ( 5 ). However, the underlying molecular mechanism by which DRβ-H inhibits malignant cells growth remains unclear.…”

Triterpenoid Saponins

“…Moreover, DRβ-H regulated the ratio of proapoptotic and antiapoptotic Bcl-2 family proteins. Furthermore, DRβ-H induced depolarization of mitochondrial membrane potential which released Apaf-1 and Cytochrome C from the inter membrane space into the cytosol, where they promoted caspase-9 and caspase-3 activation[51]. Han et al isolated five oleanane type triterpenoid saponins glycoside ST-14a, glycoside ST-J, anhuienoside E, hedra saponin B and flaccidoside II from the rhizome of Anemone flaccida and evaluated for antitumor activity on human BEL-7402 and HepG2 hepatoma cell lines, as well as the model of cervical tumor cells (HeLa) treated with lipopolysaccharide (LPS).…”