3- O-Acetyl-11-keto- β -boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma

Wan Li; Liwen Ren; Xiangjin Zheng; Jinyi Liu; Jinhua Wang; Tengfei Ji; Guanhua Du

doi:10.1016/j.apsb.2019.12.012

3- O-Acetyl-11-keto- β -boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma

Acta Pharm Sin B. 2020 Feb;10(2):301-312. doi: 10.1016/j.apsb.2019.12.012. Epub 2020 Jan 10.

Authors

Wan Li^{1

2}, Liwen Ren^{1

2}, Xiangjin Zheng^{1

2}, Jinyi Liu^{1

2}, Jinhua Wang^{1

2}, Tengfei Ji², Guanhua Du^{1

2}

Affiliations

¹ The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 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.

Abstract

Glioblastoma is the most common and aggressive primary tumor in the central nervous system, accounting for 12%-15% of all brain tumors. 3-O-Acetyl-11-keto-β-boswellic acid (AKBA), one of the most active ingredients of gum resin from Boswellia carteri Birdw., was reported to inhibit the growth of glioblastoma cells and subcutaneous glioblastoma. However, whether AKBA has antitumor effects on orthotopic glioblastoma and the underlying mechanisms are still unclear. An orthotopic mouse model was used to evaluate the anti-glioblastoma effects of AKBA. The effects of AKBA on tumor growth were evaluated using MRI. The effects on the alteration of metabolic landscape were detected by MALDI-MSI. The underlying mechanisms of autophagy reducing by AKBA treatment were determined by immunoblotting and immunofluorescence, respectively. Transmission electron microscope was used to check morphology of cells treated by AKBA. Our results showed that AKBA (100 mg/kg) significantly inhibited the growth of orthotopic U87-MG gliomas. Results from MALDI-MSI showed that AKBA improved the metabolic profile of mice with glioblastoma, while immunoblot assays revealed that AKBA suppressed the expression of ATG5, p62, LC3B, p-ERK/ERK, and P53, and increased the ratio of p-mTOR/mTOR. Taken together, these results suggested that the antitumor effects of AKBA were related to the normalization of aberrant metabolism in the glioblastoma and the inhibition of autophagy. AKBA could be a promising chemotherapy drug for glioblastoma.

Keywords: AKBA; AKBA, 3-O-acetyl-11-keto-β-boswellic acid; Autophagy; DAPI, 4′,-6-diamidino-2-phenylindole; G3P, glycerol-3-phosphate; G6P, glucose-6-phosphate; GBM, glioblastomas; GL/FFA, glycerolipid/free fatty acid; Glioblastoma; IDH1/2, isocitrate dehydrogenases 1/2; ITO, indium tin oxide; LA, linoleic acid; MALDI-MSI; MALDI-MSI, matrix-assisted laser desorption ionization-mass spectrometry imaging; NAA, N-acetyl-l-aspartic acid; NEDC, N-(1-naphthyl) ethylenediamine dihydrochloride; OA, oleic acid; PA, phosphatidic acid; PE, phosphatidylethanolamine; PG, phosphatidylglycerols; PI, phosphatidylinositol; PS, phosphatidylserine; Phospholipids; TIC, total ion current; TMZ, temozolomide.