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3-O-acetyl-11-keto-β-boswellic Acid Exerts Anti-Tumor Effects in Glioblastoma by Arresting Cell Cycle at G2/M Phase

3-O-acetyl-11-keto-β-boswellic Acid Exerts Anti-Tumor Effects in Glioblastoma by Arresting Cell Cycle at G2/M Phase

Wan Li, Jinyi Liu, Weiqi Fu, Xiangjin Zheng, Liwen Ren, Shiwei Liu, Jinhua Wang, Tengfei Ji, Guanhua Du

J Exp Clin Cancer Res. 2018 Jul 3;37(1):132.

PMID: 29970196

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP17019920	11-Keto-β-boswellic acid		17019-92-0	Price
AP67416619	3-O-Acetyl-11-keto-β-boswellic acid		67416-61-9	Price

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