Brain tumor senescence might be mediated by downregulation of S-phase kinase-associated protein 2 via butylidenephthalide leading to decreased cell viability

Abstract

Developing an effective drug for treating human glioblastoma multiform (GBM) has been investigated persistently. A pure compound butylidenephthalide (BP), isolated from Angelica sinensis, has been shown the activities to arrest the growth and initiate apoptosis of GBM in our previous reports. In this study, we further demonstrated that BP treatment accelerates the cell senescence in a dose-dependent manner in vitro and in vivo. S-phase kinase-associated protein 2 (Skp2), a proto-oncogene, is generally upregulated in cancer. We found that it was downregulated in BP-treated GBM cells. The downregulation of Skp2 is parallel with increasing p16 and p21 expression which causes G0/G1 arrest and tumor cell senescence. We also found that restoring the Skp2 protein level by exogenous overexpression prevents the BP-induced cell senescence. Therefore, the linkage between cell senescence and Skp2 expression is strengthened. Promoter binding analysis further detailed that the BP-mediated SP1 reduction might involve in the Skp2 downregulation. In summary, these results emphasize that BP-triggered senescence in GBM cells is highly associated with its control on Skp2 regulation.

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition

“…Recently, complementary medicine including TCM, have become more widely accepted as potential alternative medicines for cancer treatment. N-butylidenephthalide (BP; C 12 H 12 O 2 ) is a naturally occurring compound isolated from the extract of danggui, and has been reported to exhibit antitumor activity on various types of cancer cell, including glioblastoma multiforme [5,6], prostate cancer [7,8], lung cancer [9] and hepatoma [10]. For instance, BP down-regulates the expression of AP-2 leading to repressing transcriptional activity of hTERT and inhibits the telomerase activity in lung cancer [9].…”

“…For instance, BP down-regulates the expression of AP-2 leading to repressing transcriptional activity of hTERT and inhibits the telomerase activity in lung cancer [9]. BP down-regulates the expression of S-phase kinase-associated protein (Skp2) leading to an increase in p16 and p21 expression which cause tumor senescence and cell cycle G0/G1 arrest [5]. BP also modulates the mitochondrial-dependent and ER stress pathway, resulting in cell apoptosis [7,8].…”

Efficiency of improved RAPD and ISSR markers in assessing genetic diversity and relationships in Angelica sinensis (Oliv.) Diels varieties of China

“…In addition to effect in ameliorating female reproductive complications, A. sinensis also possess a number of other medicinal or health beneficial activities [4,5]. For example, different extracts or specific active ingredients from A. sinensis show potent anticancer activities [6,7]. Extracted natural products from A. sinensis have been proved successful also against cardiovascular complications, hepatic diseases, inflammation, etc.…”

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.…”

“…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. 2 BP inhibits telomerase activity by repressing hTERT transcriptional activity via the downregulation of Sp1 or AP-2 expression. 3,8 BP also regulates the eFAS-dependent pathway, the mitochondrial pathway, and the ER stress pathway that is involved in cell apoptosis.…”