Original articles
Wan Li, Liwen Ren, Xiangjin Zheng, Jinyi Liu, Jinhua Wang, Tengfei Ji, Guanhua Du. 3-O-Acetyl-11-keto-β-boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 301-312

3-O-Acetyl-11-keto-β-boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma
Wan Lia,b, Liwen Rena,b, Xiangjin Zhenga,b, Jinyi Liua,b, Jinhua Wanga,b, Tengfei Jib, Guanhua Dua,b
a 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;
b 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 MALDIMSI. 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.
Key words:    Glioblastoma    AKBA    MALDI-MSI    Phospholipids    Autophagy   
Received: 2019-09-27     Revised: 2019-11-02
DOI: 10.1016/j.apsb.2019.12.012
Funds: This work was supported by National Natural Science Foundation of China (No. 81573454 for Jinhua Wang and No. 81703536 for Wan Li) and supported by Beijing Natural Science Foundation (7172142,China). This work was also supported by CAMS Innovation Fund for Medical Sciences (2016-I2M-3-007, China) and Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2018ZX09711001-005-025, China).
Corresponding author: Jinhua Wang, Tengfei Ji, Guanhua Du     Email:wjh@imm.ac.cn;jitf@imm.ac.cn;dugh@imm.ac.cn
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Wan Li
Liwen Ren
Xiangjin Zheng
Jinyi Liu
Jinhua Wang
Tengfei Ji
Guanhua Du

References:
1. Iacob G, Dinca EB. Current data and strategy in glioblastoma multiforme. J Med Life 2009;2:386-93.
2. Franceschi E, Minichillo S, Brandes AA. Pharmacotherapy of glioblastoma:established treatments and emerging concepts. CNS Drugs 2017;31:675-84.
3. Nishikawa R. Standard therapy for glioblastomada review of where we are. Neurol Med Chir 2010;50:713-9.
4. Gao C, Liang J, Zhu Y, Ling C, Cheng Z, Li R, et al. Mentholmodified casein nanoparticles loading 10-hydroxycamptothecin for glioma targeting therapy. Acta Pharm Sin B 2019;9:843-57.
5. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 who classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97-109.
6. Tran B, Rosenthal MA. Survival comparison between glioblastoma multiforme and other incurable cancers. J Clin Neurosci 2010;17:417-21.
7. Ward PS, Thompson CB. Metabolic reprogramming:a cancer hallmark even warburg did not anticipate. Cancer Cell 2012;21:297-308.
8. Hsu PP, Sabatini DM. Cancer cell metabolism:Warburg and beyond. Cell 2008;134:703-7.
9. Koppenol WH, Bounds PL, Dang CV. Otto warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011;11:325-37.
10. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the warburg effect:the metabolic requirements of cell proliferation. Science 2009;324:1029-33.
11. Cancer Genome Atlas Research N, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015;372:2481-98.
12. Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 2016;164:550-63.
13. Nilsson A, Fehniger TE, Gustavsson L, Andersson M, Kenne K, Marko-Varga G, et al. Fine mapping the spatial distribution and concentration of unlabeled drugs within tissue micro-compartments using imaging mass spectrometry. PLoS One 2010;5:e11411.
14. Cornett DS, Reyzer ML, Chaurand P, Caprioli RM. Maldi imaging mass spectrometry:molecular snapshots of biochemical systems. Nat Methods 2007;4:828-33.
15. Clemis EJ, Smith DS, Camenzind AG, Danell RM, Parker CE, Borchers CH. Quantitation of spatially-localized proteins in tissue samples using MALDI-MRM imaging. Anal Chem 2012;84:3514-22.
16. Chaurand P, Norris JL, Cornett DS, Mobley JA, Caprioli RM. New developments in profiling and imaging of proteins from tissue sections by MALDI mass spectrometry. J Proteome Res 2006;5:2889-900.
17. Oppenheimer SR, Wehr AY. Imaging mass spectrometry in drug discovery and development. Bioanalysis 2015;7:2609-10.
18. Agar NY, Malcolm JG, Mohan V, Yang HW, Johnson MD, Tannenbaum A, et al. Imaging of meningioma progression by matrixassisted laser desorption ionization time-of-flight mass spectrometry. Anal Chem 2010;82:2621-5.
19. Calligaris D, Longuespee R, Debois D, Asakawa D, Turtoi A, Castronovo V, et al. Selected protein monitoring in histological sections by targeted MALDI-FTICR in-source decay imaging. Anal Chem 2013;85:2117-26.
20. Fehniger TE, Vegvari A, Rezeli M, Prikk K, Ross P, Dahlback M, et al. Direct demonstration of tissue uptake of an inhaled drug:proof-ofprinciple study using matrix-assisted laser desorption ionization mass spectrometry imaging. Anal Chem 2011;83:8329-36.
21. Wang J, Qiu S, Chen S, Xiong C, Liu H, Wang J, et al. MALDI-TOF MS imaging of metabolites with a n-(1-naphthyl) ethylenediamine dihydrochloride matrix and its application to colorectal cancer liver metastasis. Anal Chem 2015;87:422-30.
22. Ianniciello A, Rattigan KM, Helgason GV. The ins and outs of autophagy and metabolism in hematopoietic and leukemic stem cells:food for thought. Front Cell Dev Biol 2018;6:120.
23. Leone RD, Amaravadi RK. Autophagy:a targetable linchpin of cancer cell metabolism. Trends Endocrinol Metab 2013;24:209-17.
24. Liu H, Zhu G, Fan Y, Du Y, Lan M, Xu Y, et al. Natural products research in China from 2015 to 2016. Front Chem 2018;6:45.
25. Koehn FE, Carter GT. Rediscovering natural products as a source of new drugs. Discov Med 2005;5:159-64.
26. Siddiqui MZ. Boswellia serrata, a potential antiinflammatory agent:an overview. Indian J Pharm Sci 2011;73:255-61.
27. Sabina EP, Indu H, Rasool M. Efficacy of boswellic acid on lysosomal acid hydrolases, lipid peroxidation and anti-oxidant status in gouty arthritic mice. Asian Pac J Trop Biomed 2012;2:128-33.
28. Sarkate A, Dhaneshwar SS. Investigation of mitigating effect of colon-specific prodrugs of boswellic acid on 2,4,6-trinitrobenzene sulfonic acid-induced colitis in wistar rats:design, kinetics and biological evaluation. World J Gastroenterol 2017;23:1147-62.
29. Zhou X, Cai JG, Zhu WW, Zhao HY, Wang K, Zhang XF. Boswellic acid attenuates asthma phenotype by downregulation of GATA3 via inhibition of pSTAT6. Genet Mol Res 2015;14:7463-8.
30. Roy NK, Deka A, Bordoloi D, Mishra S, Kumar AP, Sethi G, et al. The potential role of boswellic acids in cancer prevention and treatment. Cancer Lett 2016;377:74-86.
31. Li W, Liu J, Fu W, Zheng X, Ren L, Liu S, et al. 3-O-Acetyl-11-keto-betaboswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase. J Exp Clin Cancer Res 2018;37:132.
32. Qin Z, Wang S, Lin Y, Zhao Y, Yang S, Song J, et al. Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice. Acta Pharm Sin B 2018;8:306-15.
33. Santos CR, Schulze A. Lipid metabolism in cancer. FEBS J 2012;279:2610-23.
34. Burdge GC, Calder PC. Introduction to fatty acids and lipids. World Rev Nutr Diet 2015;112:1-16.
35. Hay N. Reprogramming glucose metabolism in cancer:can it be exploited for cancer therapy?. Nat Rev Cancer 2016;16:635-49.
36. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 2009;457:910-4.
37. Oh-oka K, Nakatogawa H, Ohsumi Y. Physiological pH and acidic phospholipids contribute to substrate specificity in lipidation of ATG8. J Biol Chem 2008;283:21847-52.
38. Mitroi DN, Karunakaran I, Graler M, Saba JD, Ehninger D, Ledesma MD, et al. SGPL1(sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production. Autophagy 2017;13:885-99.
39. Wu W, Zhao S. Metabolic changes in cancer:beyond the warburg effect. Acta Biochim Biophys Sin 2013;45:18-26.
40. Swinnen JV, Roskams T, Joniau S, Van Poppel H, Oyen R, Baert L, et al. Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer 2002;98:19-22.
41. Chajes V, Lanson M, Fetissof F, Lhuillery C, Bougnoux P. Membrane fatty acids of breast carcinoma:contribution of host fatty acids and tumor properties. Int J Cancer 1995;63:169-75.
42. Marien E, Meister M, Muley T, Fieuws S, Bordel S, Derua R, et al. Non-small cell lung cancer is characterized by dramatic changes in phospholipid profiles. Int J Cancer 2015;137:1539-48.
43. Tan LT, Chan KG, Pusparajah P, Lee WL, Chuah LH, Khan TM, et al. Targeting membrane lipid a potential cancer cure?. Front Pharmacol 2017;8:12.
44. Fack F, Tardito S, Hochart G, Oudin A, Zheng L, Fritah S, et al. Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways. EMBO Mol Med 2017;9:1681-95.
45. Lagace TA, Ridgway ND. The role of phospholipids in the biological activity and structure of the endoplasmic reticulum. Biochim Biophys Acta 2013;1833:2499-510.
46. Patel D, Witt SN. Ethanolamine and phosphatidylethanolamine:partners in health and disease. Oxid Med Cell Longev 2017;2017:4829180.
47. Huang Q, Tan Y, Yin P, Ye G, Gao P, Lu X, et al. Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics. Cancer Res 2013;73:4992-5002.
48. Dobrzynska I, Szachowicz-Petelska B, Sulkowski S, Figaszewski Z. Changes in electric charge and phospholipids composition in human colorectal cancer cells. Mol Cell Biochem 2005;276:113-9.
49. Vance JE. Molecular and cell biology of phosphatidylserine and phosphatidylethanolamine metabolism. Prog Nucleic Acid Res Mol Biol 2003;75:69-111.
50. Zinrajh D, Horl G, Jurgens G, Marc J, Sok M, Cerne D. Increased phosphatidylethanolamine n-methyltransferase gene expression in non-small-cell lung cancer tissue predicts shorter patient survival. Oncol Lett 2014;7:2175-9.
51. Dall'Armi C, Devereaux KA, Di Paolo G. The role of lipids in the control of autophagy. Curr Biol 2013;23:R33-45.
52. Krick R, Thumm M. Atg8 lipidation is coordinated in a Ptdins3pdependent manner by the proppin Atg21. Autophagy 2016;12:2260-1.
53. Juris L, Montino M, Rube P, Schlotterhose P, Thumm M, Krick R. Pi3p binding by atg21 organises atg8 lipidation. EMBO J 2015;34:955-73.
54. Waugh MG. PIPs in neurological diseases. Biochim Biophys Acta 2015;1851:1066-82.
55. Sharma B, Kanwar SS. Phosphatidylserine:a cancer cell targeting biomarker. Semin Cancer Biol 2018;52:17-25.
56. Paine MRL, Liu J, Huang D, Ellis SR, Trede D, Kobarg JH, et al. Three-dimensional mass spectrometry imaging identifies lipid markers of medulloblastoma metastasis. Sci Rep 2019;9:2205.
57. Li S, Zhou T, Li C, Dai Z, Che D, Yao Y, et al. High metastaticgastric and breast cancer cells consume oleic acid in an AMPK dependent manner. PLoS One 2014;9:e97330.
58. Navarro-Tito N, Soto-Guzman A, Castro-Sanchez L, MartinezOrozco R, Salazar EP. Oleic acid promotes migration on MDA-MB-231 breast cancer cells through an arachidonic acid-dependent pathway. Int J Biochem Cell Biol 2010;42:306-17.
59. Jiang L, Wang W, He Q, Wu Y, Lu Z, Sun J, et al. Oleic acid induces apoptosis and autophagy in the treatment of tongue squamous cell carcinomas. Sci Rep 2017;7:11277.
60. Li H, Peng X, Wang Y, Cao S, Xiong L, Fan J, et al. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy 2016;12:1472-86.
61. Azzopardi M, Farrugia G, Balzan R. Cell-cycle involvement in autophagy and apoptosis in yeast. Mech Ageing Dev 2017;161:211-24.
62. Laggner M, Pollreisz A, Schmidinger G, Schmidt-Erfurth U, Chen YT. Autophagy mediates cell cycle response by regulating nucleocytoplasmic transport of PAX6 in limbal stem cells under ultravioletda stress. PLoS One 2017;12:e0180868.
63. White E. Autophagy and p53. Cold Spring Harb Perspect Med 2016;6:a026120.
64. Tsen AR, Long PM, Driscoll HE, Davies MT, Teasdale BA, Penar PL, et al. Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma. Int J Cancer 2014;134:1300-10.
65. Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 2014;159:1603-14.