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Effect of Embelin on TRAIL Receptor 2 mAb-induced Apoptosis of TRAIL-resistant A549 Non-small Cell Lung Cancer Cells

  • Jiang, Lei (Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University) ;
  • Hao, Jin-Li (Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University) ;
  • Jin, Mu-Lan (Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University) ;
  • Zhang, Yun-Gang (Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University) ;
  • Wei, Ping (Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University)
  • Published : 2013.10.30

Abstract

Introduction: Some non-small cell lung cancer (NSCLC) tumor cells are insensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -based therapy. This study was conducted to examine the effect of embelin on the sensitivity of the A549 NSCLC cell line to TRAIL receptor2 (TRAILR2) monoclonal antibodies and to investigate the potential mechanisms. Materials and Methods: A549 cells were treated with embelin, TRAILR2 mAb or a combination of both. Cell viability was measured using ATPlite assay and apoptosis rates were determined by flow cytometry with AnnexinV-FITC and propidium iodide staining, with the expression levels of proteins analyzed by Western blotting. Results: The cell survival rate of separate treatments with 100 ng/ml TRAILR2 antibody or 25 uM embelin were $81.5{\pm}1.57%$ and $61.7{\pm}2.84%$, respectively. Their combined use markedly decreased cell viability in A549 cells to $28.1{\pm}1.97%$ (P<0.05). The general caspase inhibitor Z-VAD-FMK could inhibit the embelin-enhanced sensitivity of A549 cells to TRAILR2 mAb ($75.97{\pm}3.17%$)(P<0.05). Both flow cytometry and cell morphological analysis showed that embelin was able to increase TRAIL-induced apoptosis in A549 cells. Combined treatment with embelin and TRAILR2 mAb augmented the activation of initiator caspases and effector caspase. In addition, A549 cells showed increasing levels of TRAILR2 protein and decreasing levels of Bcl-2, survivin and c-FLIP following the treatment with embelin+TRAILR2 mAb. Conclusions: Embelin could enhance TRAIL-induced apoptosis in A549 cells. The synergistic effect of the combination treatment might be due to modulation of multiple components in the TRAIL receptor-mediated apoptotic signaling pathway, including TRAILR2, XIAP, survivin, Bcl-2 and c-FLIP.

Keywords

References

  1. Cheng YJ, Jiang HS, Hsu SL, et al (2010). XIAP-mediated protection of H460 lung cancer cells against cisplatin. Eur J Pharmacol, 627, 75-84. https://doi.org/10.1016/j.ejphar.2009.11.003
  2. Chitra M, Sukumar E, Suja V, Devi CS (1994). Antitumor, antiinflammatory and analgesic property of embelin, a plant product. Chemotherapy, 40, 109-13. https://doi.org/10.1159/000239181
  3. Chou TC (2008). Preclinical versus clinical drug combination studies. Leuk Lymphoma, 49, 2059-80. https://doi.org/10.1080/10428190802353591
  4. Cooper WA, Kohonen-Corish MR, Zhuang L, et al (2008). Role and prognostic significance of tumor necrosis factor-related apoptosis-inducing ligand death receptor DR5 in nonsmall-cell lung cancer and precursor lesions. Cancer, 113, 135-42. https://doi.org/10.1002/cncr.23528
  5. Dai Y, Qiao L, Chan KW, et al (2009). Peroxisome proliferatoractivated receptor-gamma contributes to the inhibitory effects of Embelin on colon carcinogenesis. Cancer Res, 69, 4776-83. https://doi.org/10.1158/0008-5472.CAN-08-4754
  6. De Petris L, Crino L, Scagliotti GV, et al (2006). Treatment of advanced non-small cell lung cancer. Ann Oncol, 17, ii36-41.
  7. Duiker EW, Mom CH, de Jong S, et al (2006). The clinical trail of TRAIL. Eur J Cancer, 42, 2233-40. https://doi.org/10.1016/j.ejca.2006.03.018
  8. Fesik SW (2005). Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer, 5, 876-85. https://doi.org/10.1038/nrc1736
  9. Field JK, Duffy SW (2008). Lung cancer screening: the way forward. Br J Cancer, 99, 557-62. https://doi.org/10.1038/sj.bjc.6604509
  10. Gross A, McDonnell JM, Korsmeyer SJ (1999). BCL-2 family members and the mitochondria in apoptosis. Genes Dev, 13, 1899-911. https://doi.org/10.1101/gad.13.15.1899
  11. Holcik M, Gibson H, Korneluk RG (2001). XIAP: apoptotic brake and promising therapeutic target. Apoptosis, 6, 253-61. https://doi.org/10.1023/A:1011379307472
  12. Ihde DC, Minna JD (1991). Non-small cell lung cancer. Part II: Treatment. Curr Probl Cancer, 15, 105-54.
  13. Jo M, Kim TH, Seol DW, et al (2000). Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med, 6, 564-7. https://doi.org/10.1038/75045
  14. Kaminskyy VO, Surova OV, Piskunova T, et al (2013). Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca2+/calmodulin signaling. Cell Death Dis, 4, e522. https://doi.org/10.1038/cddis.2013.51
  15. Kim K, Fisher MJ, Xu SQ, el-Deiry WS (2000). Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin Cancer Res, 6, 335-46.
  16. Koschny R, Ganten TM, Sykora J, et al (2007). TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. Hepatology, 45, 649-58. https://doi.org/10.1002/hep.21555
  17. Lan Y, Liu X, Zhang R, et al (2013). Lithium enhances TRAIL-induced apoptosis in human lung carcinoma A549 cells. Biometals, 26, 241-54. https://doi.org/10.1007/s10534-012-9607-x
  18. Li XQ, Ke XZ, Wang YM (2012). Treatment of malignant melanoma by downregulation of XIAP and overexpression of TRAIL with a conditionally replicating oncolytic adenovirus. Asian Pac J Cancer Prev, 13, 1471-6. https://doi.org/10.7314/APJCP.2012.13.4.1471
  19. Luster TA, Carrell JA, McCormick K, et al (2009). Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib. Mol Cancer Ther, 8, 292-302. https://doi.org/10.1158/1535-7163.MCT-08-0918
  20. Mahalingam D, Szegezdi E, Keane M, et al (2009). TRAIL receptor signalling and modulation: Are we on the right TRAIL? Cancer Treat Rev, 35, 280-8. https://doi.org/10.1016/j.ctrv.2008.11.006
  21. Mori T, Doi R, Kida A, et al (2007). Effect of the XIAP inhibitor Embelin on TRAIL-induced apoptosis of pancreatic cancer cells. J Surg Res, 142, 281-6. https://doi.org/10.1016/j.jss.2007.03.068
  22. Nikolovska-Coleska Z, Xu L, Hu Z, et al (2004). Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem, 47, 2430-40. https://doi.org/10.1021/jm030420+
  23. Pore MM, Hiltermann TJ, Kruyt FA (2010). Targeting apoptosis pathways in lung cancer. Cancer Lett, 332, 359-68.
  24. Siegelin MD, Gaiser T, Siegelin Y (2009). The XIAP inhibitor Embelin enhances TRAIL-mediated apoptosis in malignant glioma cells by down-regulation of the short isoform of FLIP. Neurochem Int, 55, 423-30. https://doi.org/10.1016/j.neuint.2009.04.011
  25. Spierings DC, de Vries EG, Timens W, et al (2003). Expression of TRAIL and TRAIL death receptors in stage III non-small cell lung cancer tumors. Clin Cancer Res, 9, 3397-405.
  26. Sprick MR, Weigand MA, Rieser E, et al (2000). FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity, 12, 599-609. https://doi.org/10.1016/S1074-7613(00)80211-3
  27. Stegehuis JH, de Wilt LH, de Vries EG, et al (2009). TRAIL receptor targeting therapies for non-small cell lung cancer: current status and perspectives. Drug Resist Updat, 13, 2-15.
  28. Voortman J, Resende TP, Abou El Hassan MA, et al (2007). TRAIL therapy in non-small cell lung cancer cells: sensitization to death receptor-mediated apoptosis by proteasome inhibitor bortezomib. Mol Cancer Ther, 6, 2103-12. https://doi.org/10.1158/1535-7163.MCT-07-0167
  29. Zhang L, Fang B (2005). Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther, 12, 228-37. https://doi.org/10.1038/sj.cgt.7700792

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