Gambogic acid induces apoptotic cell death in T98G glioma cells Mya Thida a,y , Dae Won Kim b,y , Thi Thu Thuy Tran c , Minh Quan Pham c , Heesu Lee d , Inki Kim e,f,⇑ , Jae Wook Lee a,g,⇑ a Natural Product Research Center, Korea Institute of Science and Technology, Gangneung 210-340, Republic of Korea b Department of Biochemistry and Molecular Biology, Research Institute of Oral Science, College of Dentistry, Gangneung Wonju National University, Gangneung 210-702, Republic of Korea c Institute of Natural Products Research, Vietnamese Academy of Science and Technology, 18 Hoang Quoc Viet, Cay Giay, Hanoi, Viet Nam d Department of Oral Anatomy, College of Dentistry, Gangneung Wonju National University, Gangneung 210-702, Republic of Korea e Department of Medicine, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea f Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea g Department of Biological Chemistry, University of Science and Technology, Daejeun, Republic of Korea article info Article history: Received 20 August 2015 Revised 10 November 2015 Accepted 14 November 2015 Available online 14 November 2015 Keywords: Gambogic acid Reactive oxygen species (ROS) Glioblastoma Apoptosis Anticancer abstract Gambogic acid (GA), a natural product with a xanthone structure, has a broad range of anti-proliferative effects on cancer cell lines. We evaluated GA for its cytotoxic effects on T98G glioblastoma cells. GA exhibited potent anti-proliferative activity and induced apoptosis in T98G glioblastoma cells in a dose- dependent manner. Incubation of cells with GA revealed apoptotic features including increased Bax and AIF expression, cytochrome c release, and cleavage of caspase-3, -8, -9, and PARP, while Bcl-2 expres- sion was downregulated. Furthermore, GA induced reactive oxygen species (ROS) generation in T98G cells. Our results indicate that GA increases Bax- and AIF-associated apoptotic signaling in glioblastoma cells. Ó 2015 Elsevier Ltd. All rights reserved. Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor of the adult central nervous system (CNS). 1 GBM cells are derived from glial cells and have the worst prognosis among cancers. GBM cells are highly prolifer- ative, resistant to anti-cancer therapeutics, and infiltrate easily into surrounding brain tissue. The invasive glioblastoma cells infiltrate rapidly and disrupt normal tissue structure, making complete sur- gical removal of brain tumor tissue difficult. GBM treatment has not seen improvement in several decades because of these inher- ent GBM properties. The current standard treatment for malignant glioma patients is post-operational radiation therapy and chemotherapy; however, these treatments may not extend the median survival time of patients more than 14 months due to the aggressive and infiltrative nature of GBM. Chemotherapy using broad spectrum anti-cancer drugs such as cisplatin, carmustine, and temozolomide (TMZ) is the primary treatment for glioblastoma patients. These anti-cancer drugs induce malignant cell death by causing DNA damage followed by apoptosis. TMZ is an alkylating agent which is currently used as a first-line of chemotherapy for GBM treatment due to its DNA- damaging effect; however, it is not effective in all patients due to TMZ resistance. Recent studies showed that patients in which expression of the DNA repair enzyme O 6 -methylguanine DNA methyltransferase (MGMT) is silenced are relatively responsive to treatment with TMZ. TMZ resistance is caused by MGMT overex- pression related to a deficiency of methylation in the MGMT pro- moter region. 1 The resistance mechanism is generally believed to counteract chemotherapy-induced DNA alkylation. Because these treatments may not extend the median survival time of patients more than 21.7 months, the discovery of a novel anti-GBM agent is urgently required. 2 Gambogic acid (GA) is a natural product isolated from gamboge, a brownish dry resin exuded from the Garcinia hanburyi tree of Southeast Asia. Recently, GA was shown to have anti-proliferative and pro-apoptotic effects on hepatocarcinoma, 3 gastric carci- noma, 4 lung carcinoma, 5 breast cancer, 6 and glioma 7 in vivo and in vitro. Although GA has a clear inhibitory effect on the growth of various tumor cell lines by promoting apoptosis and repressing proliferation, the anti-tumor effect and the underlying mecha- nisms of GA activity against human glioblastoma are not fully understood. http://dx.doi.org/10.1016/j.bmcl.2015.11.043 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. Tel./fax: +82 2 3010 2515 (I.K.); tel.: +82 33 650 3514; fax: +82 33 650 3529 (J.W.L.). E-mail addresses: ik.kim@amc.seoul.kr (I. Kim), jwlee5@kist.re.kr (J.W. Lee). y These authors contributed equally to this work. Bioorganic & Medicinal Chemistry Letters 26 (2016) 1097–1101 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl