The natural compound n‐butylidenephthalide derived from Angelica sinensis inhibits malignant brain tumor growth in vitro and in vivo³

Abstract

The naturally-occurring compound, n-butylidenephthalide (BP), which is isolated from the chloroform extract of Angelica sinensis (AS-C), has been investigated with respect to the treatment of angina. In this study, we have examined the antitumor effects of n-butylidenephthalide on glioblastoma multiforme (GBM) brain tumors both in vitro and in vivo. In vitro, GBM cells were treated with BP, and the effects of proliferation, cell cycle and apoptosis were determined. In vivo, DBTRG-05MG, the human GBM tumor, and RG2, the rat GBM tumor, were injected subcutaneously or intracerebrally with BP. The effects on tumor growth were determined by tumor volumes, magnetic resonance imaging and survival rate. Here, we report on the potency of BP in suppressing growth of malignant brain tumor cells without simultaneous fibroblast cytotocixity. BP up-regulated the expression of Cyclin Kinase Inhibitor (CKI), including p21 and p27, to decrease phosphorylation of Rb proteins, and down-regulated the cell-cycle regulators, resulting in cell arrest at the G 0 /G 1 phase for DBTRG-05MG and RG2 cells, respectively. The apoptosis-associated proteins were dramatically increased and activated by BP in DBTRG-05MG cells and RG2 cells, but RG2 cells did not express p53 protein. In vitro results showed that BP triggered both p53-dependent and independent pathways for apoptosis. In vivo, BP not only suppressed growth of subcutaneous rat and human brain tumors but also, reduced the volume of GBM tumors in situ, significantly prolonging survival rate. These in vitro and in vivo anti-cancer effects indicate that BP could serve as a new anti-brain tumor drug.

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

“…Release of active E2F triggers the activation of a number of genes that are required for the G 0 /G 1 -S phase transition. In previous studies, regulation of p21 expression and Rb phosphorylation were shown to be responsible for cell cycle arrest in the G 0 /G 1 phase in glioma cells (Choi et al, 2008;Tsai et al, 2006). GSK3 is a multifunctional serine/threonine kinase that reg β ulates various cellular pathways involved in the cell cycle, proliferation, differentiation, and apoptosis (Blomgren et al, 2007;He et al, 2003;Miyashita et al, 2009).…”

The Induction of Orphan Nuclear Receptor Nur77 Expression by n-Butylenephthalide as Pharmaceuticals on Hepatocellular Carcinoma Cell Therapy

“…In our previous studies (Tsai et al, 2005(Tsai et al, , 2006, we demonstrated the antitumoral effects of BP on glioblastoma multiforme (GBM) brain tumors both in vitro and in vivo. In this study, we selected HepG2 and J5 HCC for further investigations because of its poor prognosis and because it requires a new strategy in clinical practice.…”

“…Diels (AS), also referred to as dong quai or danggui, a traditional Chinese medicine for menopausal symptoms (Yim et al, 2000;Ye et al, 2001a,b), has been clinically administrated for several gynecological symptoms in the United States (Abebe, 2002). In our previous study, the chloroform extract of AS and N-butylidenephthalide (BP), derived from the chloroform extract of AS, both revealed dramatic antitumor effects, causing growth arrest and apoptosis of malignant brain tumors in vitro and in vivo (Tsai et al, 2005(Tsai et al, , 2006. To date, little is known about its antitumor effects on HCC cells.…”

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

“…The natural compound n-butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been reported to have antitumor activity in glioblastoma multiforme (GBM), [1][2][3][4] prostate cancer, 5,6 oral squamous cell carcinoma, 7 lung cancer, 8 and hepatoma. 9 In particular, BP has been developed to treat brain tumors due to its ability to permeate through the blood-brain barrier and enter into the brain.…”

“…9 In particular, BP has been developed to treat brain tumors due to its ability to permeate through the blood-brain barrier and enter into the brain. 1 BP induces Nur77-mediated apoptosis via the protein kinase C/JNK pathway. 4,7,9,10 BP downregulates the expression of S-phase kinase-associated protein (Skp2), which leads to an increase in p16 and p21 expression, causing G 0 /G 1 arrest.…”