Inhibition of glioblastoma growth and angiogenesis by gambogic acid: An in vitro and in vivo study Lei Qiang a,1 , Yong Yang a,1 , Qi-Dong You b, *, Yan-Jun Ma a , Lan Yang a , Fei-Fei Nie a , Hong-Yan Gu a , Li Zhao a , Na Lu a , Qi Qi a , Wei Liu a , Xiao-Tang Wang c , Qing-Long Guo a, ** a Department of Physiology, Jiangsu Key Laboratory of Carcinogenesis and intervention, China Pharmaceutical University, Nanjing 210009, People’s Republic of China b Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People’s Republic of China c Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA 1. Introduction Glioblastoma multiforme is the most common malignant central nervous system (CNS) tumor in adults. Glioma cells show a high proliferation rate and diffusely infiltrate adjacent brain tissues [1]. Invasive glioblastoma cells rapidly infiltrate and disrupt normal tissue architecture, making complete surgical removal virtually impossible. Despite aggressive therapeutic approaches combining surgical resection, radiotherapy, and chemotherapy, the mean survival time of patients diagnosed with glio- blastoma is only 1 year [2–4]. Consequently, develop- ment of novel drug for glioblastoma multiforme is very important. biochemical pharmacology 75 (2008) 1083–1092 article info Article history: Received 26 July 2007 Accepted 28 October 2007 Keywords: Gambogic acid Apoptosis Glioblastoma Angiogenesis Caspase Mitochondrion JEL classification: Neuropharmacology abstract Gambogic acid (GA) is the major active ingredient of gamboge, a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia. The present study aims to demon- strate that gambogic acid (GA) has potent anticancer activity for glioblastoma by in vitro and in vivo study. Rat brain microvascular endothelial cells (rBMEC) were used as an in vitro model of the blood–brain barrier (BBB). To reveal an involvement of the intrinsic mitochon- drial pathway of apoptosis, the mitochondrial membrane potential and the western blot evaluation of Bax, Bcl-2, Caspase-3, caspase-9 and cytochrome c released from mitochon- dria were performed. Angiogenesis was detected by CD31 immunochemical study. The results showed that the uptake of GA by rBMEC was time-dependent, which indicated that it could pass BBB and represent a possible new target in glioma therapy. GA could cause apoptosis of rat C6 glioma cells in vitro in a concentration-dependent manner by triggering the intrinsic mitochondrial pathway of apoptosis. In vivo study also revealed that i.v. injection of GA once a day for two weeks could significantly reduce tumor volumes by antiangiogenesis and apoptotic induction of glioma cells. Collectively, the current data indicated that GA may be of potential use in treatment of glioblastoma by apoptotic induction and antiangiogenic effects. # 2007 Elsevier Inc. All rights reserved. * Corresponding author. Tel.: +86 25 83271055; fax: +86 25 83271055. ** Corresponding author. Tel.: +86 25 83271351; fax: +86 25 83271351. E-mail addresses: youqidong@gmail.com (Q.-D. You), anticancer_drug@yahoo.com.cn (Q.-L. Guo). 1 These authors contributed equally. available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/biochempharm 0006-2952/$ – see front matter # 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2007.10.033