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Enhancement of cisplatin-induced apoptosis by β-elemene in resistant human ovarian cancer cells

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Abstract

β-Elemene is a new anticancer compound extracted from the Chinese medicinal herb Rhizoma zedoariae. We have shown previously that β-elemene increases cisplatin cytotoxicity and enhances cisplatin sensitivity via blocking cell cycle progression at G2/M phase in resistant ovarian tumor cells. In the current study, we asked whether β-elemene-augmented cisplatin activity in ovarian carcinoma cells is mediated through the induction of apoptosis. Here, we show that β-elemene triggered apoptotic cell death in chemoresistant human ovarian cancer A2780/CP and MCAS cells in a dose- and time-dependent fashion, as assessed by six different apoptosis assays. Intriguingly, β-elemene was a stronger inducer of apoptosis than cisplatin in this model system, and a synergistic effect on induction of cell death was observed when the tumor cells were treated with both agents. Furthermore, β-elemene plus cisplatin exposure significantly disrupted the mitochondrial transmembrane potential (ΔΨ m) and increased the release of cytochrome c from mitochondria into the cytoplasm. The combination treatment with both compounds also induced increases in caspase-3/8/9 activities and caspase-9 cleavage, enhanced protein expression of Bax and phosphorylation of Bcl-2 at Ser-70, and reduced the protein levels of Bcl-2 and Bcl-XL in the platinum-resistant ovarian cancer cells. Taken together, these data indicate that β-elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced apoptosis and that the augmented effect of β-elemene on cisplatin cytotoxicity and sensitivity in resistant ovarian tumor cells is mediated through a mitochondria- and caspase-dependent cell death pathway.

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References

  1. Sfakianos GP, Havrilesky LJ. A review of cost-effectiveness studies in ovarian cancer. Cancer Control. 2010;18:59–64.

    Google Scholar 

  2. Murphy G. Cancer statistics. CA Cancer J Clin. 2000;50:7–33.

    Article  Google Scholar 

  3. Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov. 2005;4:307–20.

    Article  PubMed  CAS  Google Scholar 

  4. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7:573–84.

    Article  PubMed  CAS  Google Scholar 

  5. Li X, Wang G, Zhao J, Ding H, Cunningham C, Chen F, Flynn DC, Reed E, Li QQ. Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase. Cell Mol Life Sci. 2005;62:894–904.

    Article  PubMed  CAS  Google Scholar 

  6. Li QQ, Wang G, Zhang M, Cuff CF, Huang L, Reed E. beta-Elemene, a novel plant-derived antineoplastic agent, increases cisplatin chemosensitivity of lung tumor cells by triggering apoptosis. Oncol Rep. 2009;22:161–70.

    PubMed  CAS  Google Scholar 

  7. Li QQ, Wang G, Huang F, Banda M, Reed E. Antineoplastic effect of beta-elemene on prostate cancer cells and other types of solid tumour cells. J Pharm Pharmacol. 2010;62:1018–27.

    Article  PubMed  CAS  Google Scholar 

  8. Li QQ, Wang G, Reed E, Huang L, Cuff CF. Evaluation of Cisplatin in Combination with beta-Elemene as a Regimen for Prostate Cancer Chemotherapy. Basic Clin Pharmacol Toxicol. 2010;107:868–76.

    Article  PubMed  CAS  Google Scholar 

  9. Zhao J, Li QQ, Zou B, Wang G, Li X, Kim JE, Cuff CF, Huang L, Reed E, Gardner K. In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinoma. Int J Oncol. 2007;31:241–52.

    PubMed  CAS  Google Scholar 

  10. Wang G, Li X, Huang F, Zhao J, Ding H, Cunningham C, Coad JE, Flynn DC, Reed E, Li QQ. Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death. Cell Mol Life Sci. 2005;62:881–93.

    Article  PubMed  CAS  Google Scholar 

  11. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–19.

    Article  PubMed  CAS  Google Scholar 

  12. Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003;4:552–65.

    Article  PubMed  CAS  Google Scholar 

  13. Ellis M, Yuan J, Horvitz H. Mechanisms and function of cell death. Annu Rev Cell Biol. 1991;7:663–98.

    Article  PubMed  CAS  Google Scholar 

  14. Thompson C. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267:1456–62.

    Article  PubMed  CAS  Google Scholar 

  15. Steller H. Mechanisms and genes of cellular suicide. Science. 1995;267:1445–9.

    Article  PubMed  CAS  Google Scholar 

  16. Li J, Feng Q, Kim J-M, Li M, Fung FK, Tsang BK. Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. Endocrinology. 2001;142:370–80.

    Article  PubMed  CAS  Google Scholar 

  17. MacFarlane M. Cell death pathways–potential therapeutic targets. Xenobiotica. 2009;39:616–24.

    Article  PubMed  CAS  Google Scholar 

  18. Wyllie A. Apoptosis and carcinogenesis. Eur J Cell Biol. 1997;73:189–97.

    PubMed  CAS  Google Scholar 

  19. Selzner M, Bielawska A, Morse M, Rudiger H, Sindram D, Hannun Y, Clavien P. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res. 2001;61:1233–40.

    PubMed  CAS  Google Scholar 

  20. Serrano M, Sanchez-Rovira P, Algarra I, Jaen A, Lozano A, Gaforio J. Evaluation of a gemcitabine-doxorubicin-paclitaxel combination schedule through flow cytometry assessment of apoptosis extent induced in human breast cancer cell lines. Jpn J Cancer Res. 2002;93:559–66.

    Article  PubMed  CAS  Google Scholar 

  21. Pathania D, Millard M, Neamati N. Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv Drug Deliv Rev. 2009;61:1250–75.

    Article  PubMed  CAS  Google Scholar 

  22. Galluzzi L, Morselli E, Kepp O, Vitale I, Rigoni A, Vacchelli E, Michaud M, Zischka H, Castedo M, Kroemer G. Mitochondrial gateways to cancer. Mol Aspects Med. 2010;31:1–20.

    Article  PubMed  CAS  Google Scholar 

  23. Xu CX, Jin H, Cho MH Apoptosis and apoptosis-based therapy in lung cancer. Anticancer Agents Med Chem. 2009;9:952–7.

    Article  PubMed  CAS  Google Scholar 

  24. Wang C, Youle RJ. The role of mitochondria in apoptosis. Annu Rev Genet. 2009;43:95–118.

    Article  PubMed  CAS  Google Scholar 

  25. Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9:537–49.

    Article  PubMed  CAS  Google Scholar 

  26. Fraser M, Leung B, Jahani-Asl A, Yan X, Thompson W, Tsang B. Chemoresistance in human ovarian cancer: the role of apoptotic regulators. Reprod Biol Endocrinol. 2003;1:66.

    Article  PubMed  Google Scholar 

  27. Behrens BC, Hamilton TC, Masuda H, Grotzinger KR, Whang-Peng J, Louie KG, Knutsen T, McKoy WM, Young RC, Ozols RF. Characterization of a cis-diamminedichloroplatinum (II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues. Cancer Res. 1987;47:414–8.

    PubMed  CAS  Google Scholar 

  28. Parker RJ, Eastman A, Bostick-Bruton F, Reed E. Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced DNA repair of cisplatin-DNA lesions and reduced drug accumulation. J Clin Invest. 1991;87:773–7.

    Article  Google Scholar 

  29. Kitabayashi A, Hirokawa M, Hatano Y, Lee M, Kuroki J, Miura A. Granulocyte colony-stimulating factor down-regulates allogeneic immune responses by post-transcriptional inhibition of tumor necrosis factor- production. Blood. 1995;86:2220.

    PubMed  CAS  Google Scholar 

  30. Sasaki H, Sheng Y, Kotsuji F, Tsang B. Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Res. 2000;60:5659–66.

    PubMed  CAS  Google Scholar 

  31. Ho YS, Duh JS, Jeng JH, Wang YJ, Liang YC, Lin CH, Tseng CJ, Yu CF, Chen RJ, Lin JK. Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2/M cell cycle arrest in human colorectal cancer cells. Int J Cancer. 2001;91:393–401.

    Article  PubMed  CAS  Google Scholar 

  32. Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, Halayko AJ, Los M. Apoptosis and cancer: mutations within caspase genes. J Med Genet. 2009;46:497–510.

    Article  PubMed  CAS  Google Scholar 

  33. Ledgerwood EC, Morison IM. Targeting the apoptosome for cancer therapy. Clin Cancer Res. 2009;15:420–4.

    Article  PubMed  CAS  Google Scholar 

  34. Ashkenazi A, Dixit V. Death receptors: signaling and modulation. Science. 1998;281:1305–8.

    Article  PubMed  CAS  Google Scholar 

  35. Nunez G, Benedict M, Hu Y, Inohara N. Caspases: the proteases of the apoptotic pathway. Oncogene. 1998;17:3237–45.

    Article  PubMed  Google Scholar 

  36. Stennicke H, Jurgensmeier J, Shin H, Deveraux Q, Wolf B, Yang X, Zhou Q, Ellerby H, Ellerby L, Bredesen D, Green D, Reed J, Froelich C, Salvesen G. Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem. 1998;273:27084–90.

    Article  PubMed  CAS  Google Scholar 

  37. Deng Y, Lin Y, Wu X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev. 2002;16:33–45.

    Article  PubMed  CAS  Google Scholar 

  38. Grunewald S, Sharma R, Paasch U, Glander HJ, Agarwal A. Impact of caspase activation in human spermatozoa. Microsc Res Tech, 2009;72:878–88.

    Article  PubMed  CAS  Google Scholar 

  39. Suen DF, Norris KL, Youle RJ. Mitochondrial dynamics and apoptosis. Genes Dev. 2008;22:1577–90.

    Article  PubMed  CAS  Google Scholar 

  40. Colin J, Gaumer S, Guenal I, Mignotte B. Mitochondria, Bcl-2 family proteins and apoptosomes: of worms, flies and men. Front Biosci. 2009;14:4127–37.

    Article  PubMed  CAS  Google Scholar 

  41. Jourdain A, Martinou JC. Mitochondrial outer-membrane permeabilization and remodelling in apoptosis. Int J Biochem Cell Biol. 2009;41:1884–9.

    Article  PubMed  CAS  Google Scholar 

  42. Zamzami N, Susin S, Marchetti P, et al. Mitochondrial control of nuclear apoptosis. J Exp Med. 1996;183:1533–44.

    Article  PubMed  CAS  Google Scholar 

  43. Green D, Reed J. Mitochondria and apoptosis. Science. 1998;281:1309–12.

    Article  PubMed  CAS  Google Scholar 

  44. Liu X, Kim C, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–57.

    Article  PubMed  CAS  Google Scholar 

  45. Zoratti M, Szabo I. The mitochondrial permeability transition. Biochim Biophys Acta. 1995;1241:139–76.

    Article  PubMed  Google Scholar 

  46. Jacobson M, Weil M, Raff M. Programmed cell death in animal development. Cell. 1997;88:347–54.

    Article  PubMed  CAS  Google Scholar 

  47. Mandlekar S. Y. R., Tan TH, Kong AN. Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells. Cancer Res. 2000;60:5995–6000.

    PubMed  CAS  Google Scholar 

  48. Fulda S. Caspase-8 in cancer biology and therapy. Cancer Lett. 2009;281:128–33.

    Article  PubMed  CAS  Google Scholar 

  49. Sun S, Yue P, Hong W, Lotan R. Augmentation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) through up-regulation of TRAIL receptors in human lung cancer cells. Cancer Res. 2000;60:7149–55.

    PubMed  CAS  Google Scholar 

  50. Thornberry N, Lazebnik Y. Caspases. Enemies within. Science. 1998;281:1312–6.

    Article  PubMed  CAS  Google Scholar 

  51. Petronilli V, Costantini P, Scorrano L, Colonna R, Passamonti S, Bernardi P. The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols: increase of the gating potential by oxidants and its reversal by reducing agents. J Biol Chem. 1994;269:16638–42.

    PubMed  CAS  Google Scholar 

  52. Kuo HM, Tsai HC, Lin YL, Yang JS, Huang AC, Yang MD, Hsu SC, Chung MC, Gibson Wood W, Chung JG. Mitochondrial-dependent caspase activation pathway is involved in baicalein-induced apoptosis in human hepatoma J5 cells. Int J Oncol. 2009;35:717–24.

    PubMed  CAS  Google Scholar 

  53. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009;15:1126–32.

    Article  PubMed  CAS  Google Scholar 

  54. Szegezdi E, Macdonald DC, Ni Chonghaile T, Gupta S, Samali A. Bcl-2 family on guard at the ER. Am J Physiol Cell Physiol. 2009;296:C941–53.

    Article  PubMed  CAS  Google Scholar 

  55. Srivastava R, Mi Q, Hardwick J, Longo D. Deletion of the loop region of Bcl-2 completely blocks paclitaxel-induced apoptosis. Proc Natl Acad Sci USA. 1999;96:3775–80.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This publication was made possible by grants from the Natural Science Foundation of Science and Technology Department of Guangxi Province (No. 0991294) and the Guangxi Scientific Research and Technological Development Program (No. 200901059), and by grants from the National Institutes of Health (Nos. P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003) and West Virginia University School of Medicine Research Grant (to Q. Q. Li).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Beihai Institute of Endocrine and Metabolic Diseases, Beihai, 536000, Guangxi, China

    Qingdi Quentin Li, Huasheng Liang & Yuhua Zhong

  2. West Virginia University Cancer Center, Morgantown, WV, 26506, USA

    Qingdi Quentin Li, Rebecca X. Lee & Eddie Reed

  3. National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Qingdi Quentin Li

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  1. Qingdi Quentin Li
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  2. Rebecca X. Lee
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  3. Huasheng Liang
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  4. Yuhua Zhong
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  5. Eddie Reed
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Corresponding authors

Correspondence to Qingdi Quentin Li or Yuhua Zhong.

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Qingdi Li, Rebecca Lee, and Huasheng Liang contributed equally to this work.

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Li, Q.Q., Lee, R.X., Liang, H. et al. Enhancement of cisplatin-induced apoptosis by β-elemene in resistant human ovarian cancer cells. Med Oncol 30, 424 (2013). https://doi.org/10.1007/s12032-012-0424-4

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