Abstract
Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells) and human hepatocellular carcinoma (Hep-G2 cells). Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM) U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP) family members,(e.g., survivin and XIAP) by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM.
Highlights
Glioblastoma multiforme (GBM, WHO IV) represents approximately 30% of all types of primary brain tumors and remains the leading cause of cancer related death induced by malignant intracranial diseases [1]
To evaluate the cytotoxic effect of saponin 1 on glioblastoma U251MG and U87MG cells, cells were treated with saponin 1 at uniform-gradient concentrations followed by cell viability measurements using the MTT assay at 24 h and 72 h, respectively
The growth inhibitory dose of 50% (ID50) of saponin 1 was 7.4 μg/ml in U251MG cells and 8.6 μg/ml in U87MG cells
Summary
Glioblastoma multiforme (GBM, WHO IV) represents approximately 30% of all types of primary brain tumors and remains the leading cause of cancer related death induced by malignant intracranial diseases [1]. The clinical benefits are still insufficient because genetic heterogeneity is observed in individual patients and the effectiveness of current chemotherapeutic agents is based on single molecular targets, which can be gradually overcomed as a result of compensation from alternative pro-survival signaling pathways [4]. There is an unmet need to develop novel chemotherapeutic agents that target multiple molecular pathways to inhibit pro-survival signals and induce apoptosis in the treatment of glioblastoma multiforme (GBM). It has been shown that the inactivation of many essential enzymes in the pro-survival signaling pathways, including the Phosphoinositide 3-kinase (PI3K)/Protein Kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway [10] and the NF-κB signaling pathway, and the down-regulation of some key apoptotic mediators in the IAP family and Bcl-2 family contribute principally to the inhibition of cancer cell proliferation and the induction of apoptosis by these active compounds
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