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Glioma progression is suppressed by Naringenin and APO2L combination therapy via the activation of apoptosis in vitro and in vivo

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Summary

Naringenin (NG) is a natural antioxidant flavonoid which is isolated from citrus fruits, and has been reported to inhibit colon cancer proliferation. However, the effects of NG treatment on glioma remain to be elucidated. The present study aimed to explore the effects of NG on glioma in vitro and in vivo. Also, the interactions between NG and APO2 ligand (APO2L; also known as tumor necrosis factor-related apoptosis-inducing ligand) were investigated in glioma. A synergistic effect of NG and APO2L combination on apoptotic induction was observed, though glioma cells were insensitive to APO2L alone. After NG treatment, glioma cells resumed the sensitivity to APO2L and cell apoptosis was induced via the activation of caspases, elevation of decoy receptors 4 and 5 (DR4 and DR5) and induction of p53. Coadministration of NG and APO2L decreased levels of anti-apoptotic B cell lymphoma 2 (Bcl-2) family members Bcl-2 and Bcl-extra large (Bcl-xL), while increased levels of proapoptotic factors Bcl-2-associated agonist of cell death (Bad) and Bcl-2 antagonist/killer 1 (Bak). Furthermore, an in vivo mouse xenograft model demonstrated that NG and APO2L cotreatment markedly suppressed glioma growth by activating apoptosis in tumor tissues when compared with NG or APO2L monotherapy. The present study provides a novel therapeutic strategy for glioma by potentiating APO2L-induced apoptosis via the combination with NG in glioma tumor cells.

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Availability of data and material

Materials described in the manuscript and the datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, Hegi ME (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51

    CAS  PubMed  Google Scholar 

  2. Westphal M, Lamszus K (2011) The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. Nat Rev Neurosci 12:495–508

    CAS  PubMed  Google Scholar 

  3. Cuddapah VA, Robel S, Watkins S, Sontheimer H (2014) A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15:455–465

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Okada H, Kohanbash G, Zhu X, Kastenhuber ER, Hoji A, Ueda R, Fujita M (2009) Immunotherapeutic approaches for glioma. Crit Rev Immunol 29:1–42

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Daga A, Bottino C, Castriconi R, Gangemi R, Ferrini S (2011) New perspectives in glioma immunotherapy. Curr Pharm Des 17:2439–2467

    CAS  PubMed  Google Scholar 

  6. Jovčevska I, Kočevar N, Komel R (2013) Glioma and glioblastoma - how much do we (not) know? Mol Clin Oncol 1:935–941

    PubMed  PubMed Central  Google Scholar 

  7. Yang FY, Teng MC, Lu M, Liang HF, Lee YR, Yen CC, Liang ML, Wong TT (2012) Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound. Int J Nanomedicine 7:965–974

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ali SA, McHayleh WM, Ahmad A, Sehgal R, Braffet M, Rahman M, Bejjani G, Friedland DM (2008) Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases. J Neurosurg 109:268–272

    CAS  PubMed  Google Scholar 

  9. Zhou J, Atsina KB, Himes BT, Strohbehn GW, Saltzman WM (2012) Novel delivery strategies for glioblastoma. Cancer J 18:89–99

    PubMed  Google Scholar 

  10. Mao H, Lebrun DG, Yang J, Zhu VF, Li M (2012) Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Investig 30:48–56

    Google Scholar 

  11. Liu Y, Shete S, Hosking F, Robertson L, Houlston R, Bondy M (2010) Genetic advances in glioma: susceptibility genes and networks. Curr Opin Genet Dev 20:239–244

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT, Schmittling RJ, Nair SK, Reap EA, Norberg PK, Herndon JE, Kuan CT, Morgan RA, Rosenberg SA, Johnson LA (2014) EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res 20:972–984

    CAS  PubMed  Google Scholar 

  13. Kim JY, Koo HM, Kim DS (2001) Development of C-20 modified betulinic acid derivatives as antitumor agents. Bioorg Med Chem Lett 11:2405–2408

    CAS  PubMed  Google Scholar 

  14. Mertens-Talcott SU, Noratto GD, Li X, Angel-Morales G, Bertoldi MC, Safe S (2013) Betulinic acid decreases ER-negative breast cancer cell growth in vitro and in vivo: role of Sp transcription factors and microRNA-27a: ZBTB10. Mol Carcinog 52:591–602

    CAS  PubMed  Google Scholar 

  15. Potze L, Mullauer FB, Colak S, Kessler JH, Medema JP (2014) Betulinic acid-induced mitochondria-dependent cell death is counterbalanced by an autophagic salvage response. Cell Death Dis 5:e1169

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Gao M, Lau PM, Kong SK (2014) Mitochondrial toxin betulinic acid induces in vitro eryptosis in human red blood cells through membrane permeabilization. Arch Toxicol 88:755–768

    CAS  PubMed  Google Scholar 

  17. Potze L, di Franco S, Kessler JH, Stassi G, Medema JP (2016) Betulinic acid kills colon cancer stem cells. Curr Stem Cell Res Ther 11:427–433

    CAS  PubMed  Google Scholar 

  18. Majeed R, Sangwan PL, Chinthakindi PK, Khan I, Dangroo NA, Thota N, Hamid A, Sharma PR, Saxena AK, Koul S (2013) Synthesis of 3-O-propargylated betulinic acid and its 1,2,3-triazoles as potential apoptotic agents. Eur J Med Chem 63:782–792

    CAS  PubMed  Google Scholar 

  19. MacFarlane M (2003) TRAIL-induced signalling and apoptosis. Toxicol Lett 139:89–97

    CAS  PubMed  Google Scholar 

  20. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM (1997) An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277:815–818

    CAS  PubMed  Google Scholar 

  21. Mellier G, Huang S, Shenoy K, Pervaiz S (2010) TRAILing death in cancer. Mol Asp Med 31:93–112

    CAS  Google Scholar 

  22. Zhang L, Fang B (2005) Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 12:228–237

    CAS  PubMed  Google Scholar 

  23. Jin CY, Park C, Cheong J, Choi BT, Lee TH, Lee JD, Lee WH, Kim GY, Ryu CH, Choi YH (2007) Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3. Cancer Lett 257:56–64

    CAS  PubMed  Google Scholar 

  24. Nam SY, Jung GA, Hur GC, Chung HY, Kim WH, Seol DW, Lee BL (2003) Upregulation of FLIP(S) by Akt, a possible inhibition mechanism of TRAIL-induced apoptosis in human gastric cancers. Cancer Sci 94:1066–1073

    CAS  PubMed  Google Scholar 

  25. Stindt MH, Muller PAJ, Ludwig RL, Kehrloesser S, Dötsch V, Vousden KH (2015) Functional interplay between MDM2, p63/p73 and mutant p53. Oncogene 34:4300–4310

    CAS  PubMed  Google Scholar 

  26. Hock AK, Vousden KH (2012) Tumor suppression by p53: fall of the triumvirate? Cell 149:1183–1185

    CAS  PubMed  Google Scholar 

  27. Gonzalvez F, Ashkenazi A (2010) New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 29:4752–4765

    CAS  PubMed  Google Scholar 

  28. Kong R, Jia G, Cheng ZX, Wang YW, Mu M, Wang SJ, Pan SH, Gao Y, Jiang HC, Dong DL, Sun B (2012) Dihydroartemisinin enhances Apo2L/TRAIL-mediated apoptosis in pancreatic cancer cells via ROS-mediated up-regulation of death receptor 5. PLoS One 7:e37222

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mitsiades CS, Treon SP, Mitsiades N, Shima Y, Richardson P, Schlossman R, Hideshima T, Anderson KC (2001) TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 98:795–804

    CAS  PubMed  Google Scholar 

  30. Schneckenburger H, Weber P, Wagner M, Schickinger S, Richter V, Bruns T, Strauss WS, Wittig R (2012) Light exposure and cell viability in fluorescence microscopy. J Microsc 245:311–318

    CAS  PubMed  Google Scholar 

  31. Li JM, Ge CX, Xu MX, Wang W, Yu R, Fan CY, Kong LD (2015) Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats. Mol Nutr Food Res 59:189–202

    CAS  PubMed  Google Scholar 

  32. Xu MX, Yu R, Shao LF, Zhang YX, Ge CX, Liu XM, Wu WY, Li JM, Kong LD (2016) Up-regulated fractalkine (FKN) and its receptor CX3CR1 are involved in fructose-induced neuroinflammation: suppression by curcumin. Brain Behav Immun 58:69–81

    CAS  PubMed  Google Scholar 

  33. Li Y, Huang W, Huang S, Du J, Huang C (2012) Screening of anti-cancer agent using zebrafish: comparison with the MTT assay. Biochem Biophys Res Commun 422:85–90

    CAS  PubMed  Google Scholar 

  34. Wang W, Ding XQ, Gu TT, Song L, Li JM, Xue QC, Kong LD (2015) Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377. Free Radic Biol Med 83:214–226

    CAS  PubMed  Google Scholar 

  35. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408

    CAS  PubMed  Google Scholar 

  36. Lingaraju MC, Pathak NN, Begum J, Balaganur V, Bhat RA, Ramachandra HD, Ayanur A, Ram M, Singh V, Kumar D, Kumar D, Tandan SK (2015) Betulinic acid attenuates lung injury by modulation of inflammatory cytokine response in experimentally-induced polymicrobial sepsis in mice. Cytokine 71:101–108

    CAS  PubMed  Google Scholar 

  37. Kawahara T, Toso C, Yamaguchi K, Cader S, Douglas DN, Nourbakhsh M, Lewis JT, Churchill TA, Yagita H, Kneteman NM (2013) Additive effect of sirolimus and anti-death receptor 5 agonistic antibody against hepatocellular carcinoma. Liver Int 33:1441–1448

    CAS  PubMed  Google Scholar 

  38. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726

    CAS  PubMed  Google Scholar 

  39. Cazzola M, Segreti A, Matera MG (2013) New developments in the combination treatment of COPD: focus on umeclidinium/vilanterol. Drug Des Devel Ther 7:1201–1208

    PubMed  PubMed Central  Google Scholar 

  40. Healy S, O'Leary L, Szegezdi E (2015) An added dimension to tumour TRAIL sensitivity. Oncoscience 2:906–907

    PubMed  PubMed Central  Google Scholar 

  41. Moldoveanu T, Follis AV, Kriwacki RW, Green DR (2014) Many players in BCL-2 family affairs. Trends Biochem Sci 39:101–111

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F, Jacks T (2002) p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416:560–564

    CAS  PubMed  Google Scholar 

  43. Dillon CP, Oberst A, Weinlich R, Janke LJ, Kang TB, Ben-Moshe T, Mak TW, Wallach D, Green DR (2012) Survival function of the FADD-CASPASE-8-cFLIP(L) complex. Cell Rep 1:401–407

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Hunan Provincial Natural Science Foundation of China (No. 2018JJ3773).

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Authors and Affiliations

  1. Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China

    Tao Song, Mingyu Zhang, Jun Wu, Fenghua Chen, Ying Wang & Yujie Ma

  2. Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, China

    Zhijie Dai

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  1. Tao Song
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The study was approved by the Ethics Committee of Xiangya Hospital of Central South University (Changsha, China). All applicable international, national, institutional guidelines for the care and use of animals were followed.

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Song, T., Zhang, M., Wu, J. et al. Glioma progression is suppressed by Naringenin and APO2L combination therapy via the activation of apoptosis in vitro and in vivo. Invest New Drugs 38, 1743–1754 (2020). https://doi.org/10.1007/s10637-020-00979-2

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