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J Exp Clin Cancer Res. 2018 Jul 3;37(1):132. doi: 10.1186/s13046-018-0805-4.

3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase.

Li W1,2, Liu J2,3, Fu W1,2, Zheng X1,2, Ren L1,2, Liu S4, Wang J5,6, Ji T7, Du G8,9.

Author information

1
The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China.
2
Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
3
Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650500, China.
4
Department of Endocrinology, Shanxi DAYI Hospital, Shanxi Medical University, Taiyuan, 030002, Shanxi, China.
5
The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China. wjh@imm.ac.cn.
6
Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. wjh@imm.ac.cn.
7
The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China. jitf@imm.ac.cn.
8
The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China. dugh@imm.ac.cn.
9
Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. dugh@imm.ac.cn.

Abstract

BACKGROUND:

Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults accounting for about 50% of all gliomas. Up to now, the chemotherapy approaches for GBM were limited. 3-O-acetyl-11-keto-β-boswellic acid (AKBA), the major active ingredient of the gum resin from Boswellia serrata and Boswellia carteri Birdw., was reported to inhibit the growth of many types of cancer cells; however, the underlying mechanism of its anticancer effects are still unclear.

METHODS:

The effects of AKBA on cell viability and its cytotoxicity were determined using CCK8 and LDH kits respectively. The EdU-DNA synthesis assay was used to evaluate inhibition of cell proliferation by AKBA. The role of AKBA in glioblastoma cell functions such as migration/invasion, and colony formation was evaluated using transwell chambers and soft agar, respectively. Flow cytometry and western blotting were used to detect AKBA-induced apoptosis. Potential mechanisms of AKBA action were explored by RNA sequencing and the identified hub genes were validated by real-time quantitative PCR and western blotting. Finally, the in vivo anti-tumor activity of AKBA was evaluated against a human glioblastoma cell line, U87-MG, in a xenograft mouse model.

RESULTS:

AKBA inhibited cell proliferation, caused the release of LDH, decreased DNA synthesis, and inhibited the migration, invasion, and colony formation of U251 and U87-MG human glioblastoma cell lines. AKBA increased apoptosis as well as the activity of caspase 3/7 and the protein expression of cleaved-caspase 3 and cleaved PARP, while decreasing mitochondrial membrane potential. RNA-sequencing analyses showed that AKBA suppressed the expression of pRB, FOXM1, Aurora A, PLK1, CDC25C, p-CDK1, cyclinB1, Aurora B, and TOP2A while increasing the expression of p21 and GADD45A. These findings were validated by qRT-PCR and western blotting. The data are consistent with a mechanism in which AKBA arrested the cell cycle in glioblastoma cells at the G2/M phase by regulating the p21/FOXM1/cyclin B1 pathway, inhibited mitosis by downregulating the Aurora B/TOP2A pathway, and induced mitochondrial-dependent apoptosis. Oral administration of AKBA (100 mg/kg) significantly suppressed the tumorigenicity of U87-MG cells in a xenograft mouse model.

CONCLUSIONS:

Taken together, these results suggest that AKBA (molecular weight, 512.7 Da) might be a promising chemotherapy drug in the treatment of GBM.

KEYWORDS:

AKBA; Apoptosis; Cell cycle; Glioblastoma; p21/FOXM1/cyclin B1

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