Tumor Biology

, Volume 36, Issue 4, pp 2937–2945 | Cite as

Lycorine induces programmed necrosis in the multiple myeloma cell line ARH-77

  • Yuhao Luo
  • Mridul Roy
  • Xiaojuan Xiao
  • Shuming Sun
  • Long Liang
  • Huiyong Chen
  • Yin Fu
  • Yang Sun
  • Min Zhu
  • Mao Ye
  • Jing Liu
Research Article

Abstract

Lycorine, a natural alkaloid, has been widely reported to possess potential efficacy against cancer. However, the anti-multiple myeloma mechanism of lycorine is not fully understood. In this study, the results demonstrated that lycorine is effective against multiple myeloma cell line ARH-77 via inducing programmed necrosis. The mechanisms of lycorine on the multiple myeloma cell line ARH-77 are associated with G1 phase cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) generation, ATP depletion, and DNA damage. Our results elucidate the new mechanism of lycorine against multiple myeloma.

Keywords

Lycorine ARH-77 cell ROS generation ATP depletion DNA damage Programmed necrosis 

Notes

Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81270576, 81301710, 31101686), New Century Excellent Talents in University (NCET-11-0518), and Doctoral Fund of the Ministry of Education of China (No. 20120162110054).

Conflicts of interest

None

References

  1. 1.
    Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128.CrossRefPubMedGoogle Scholar
  2. 2.
    Chanan-Khan AA, San Miguel JF, Jagannath S, Ludwig H, Dimopoulos MA. Novel therapeutic agents for the management of patients with multiple myeloma and renal impairment. Clin Cancer Res. 2012;18(8):2145–63.CrossRefPubMedGoogle Scholar
  3. 3.
    Giralt S. Stem cell transplantation for multiple myeloma: current and future status. Hematology. 2012;17 Suppl 1:S117–20.PubMedGoogle Scholar
  4. 4.
    Mariz JM, Esteves GV. Review of therapy for relapsed/refractory multiple myeloma: focus on lenalidomide. Curr Opin Oncol. 2012;24(2):S3–11.CrossRefPubMedGoogle Scholar
  5. 5.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.CrossRefPubMedGoogle Scholar
  6. 6.
    Markert CL. Neoplasia: a disease of cell differentiation. Cancer Res. 1968;28(9):1908–14.PubMedGoogle Scholar
  7. 7.
    Panaretakis T, Pokrovskaja K, Shoshan MC, Grander D. Interferon-alpha-induced apoptosis in U266 cells is associated with activation of the proapoptotic Bcl-2 family members bak and bax. Oncogene. 2003;22(29):4543–56.CrossRefPubMedGoogle Scholar
  8. 8.
    Stromberg T, Dimberg A, Hammarberg A, Carlson K, Osterborg A, Nilsson K, et al. Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood. 2004;103(8):3138–47.CrossRefPubMedGoogle Scholar
  9. 9.
    Khan SB, Maududi T, Barton K, Ayers J, Alkan S. Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma. Br J Haematol. 2004;125(2):156–61.CrossRefPubMedGoogle Scholar
  10. 10.
    Park WH, Seol JG, Kim ES, Hyun JM, Jung CW, Lee CC, et al. Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res. 2000;60(11):3065–71.PubMedGoogle Scholar
  11. 11.
    Liu Q, Hilsenbeck S, Gazitt Y. Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. Blood. 2003;101(10):4078–87.CrossRefPubMedGoogle Scholar
  12. 12.
    Gottesman MM. How cancer cells evade chemotherapy: sixteenth Richard and Hinda Rosenthal Foundation award lecture. Cancer Res. 1993;53(4):747–54.PubMedGoogle Scholar
  13. 13.
    Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27.CrossRefPubMedGoogle Scholar
  14. 14.
    Oancea M, Mani A, Hussein MA, Almasan A. Apoptosis of multiple myeloma. Int J Hematol. 2004;80(3):224–31.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wu M, Jiang Z, Duan H, Sun L, Zhang S, Chen M, et al. Deoxypodophyllotoxin triggers necroptosis in human non-small cell lung cancer NCI-H460 cells. Biomed Pharmacother. 2013;67(8):701–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Fu Z, Deng B, Liao Y, Shan L, Yin F, Wang Z, et al. The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis. BMC Cancer. 2013;13(580):1471–2407.Google Scholar
  17. 17.
    Basit F, Cristofanon S, Fulda S. Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes. Cell Death Differ. 2013;20(9):1161–73.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Pasupuleti N, Leon L, Carraway 3rd KL, Gorin F. 5-Benzylglycinyl-amiloride kills proliferating and nonproliferating malignant glioma cells through caspase-independent necroptosis mediated by apoptosis-inducing factor. J Pharmacol Exp Ther. 2013;344(3):600–15.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Park EJ, Min KJ, Lee TJ, Yoo YH, Kim YS. Kwon TK: beta-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells. Cell Death Dis. 2014;15(5):202.Google Scholar
  20. 20.
    Amaravadi RK, Thompson CB. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res. 2007;13(24):7271–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 2004;18(11):1272–82.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Artal-Sanz M, Tavernarakis N. Proteolytic mechanisms in necrotic cell death and neurodegeneration. FEBS Lett. 2005;579(15):3287–96.CrossRefPubMedGoogle Scholar
  23. 23.
    Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116(2):205–19.CrossRefPubMedGoogle Scholar
  24. 24.
    Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1(2):112–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4(5):313–21.CrossRefPubMedGoogle Scholar
  26. 26.
    He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137(6):1100–11.CrossRefPubMedGoogle Scholar
  27. 27.
    Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325(5938):332–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Hu X, Han W, Li L. Targeting the weak point of cancer by induction of necroptosis. Autophagy. 2007;3(5):490–2.CrossRefPubMedGoogle Scholar
  29. 29.
    Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J. A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci U S A. 2009;106(29):11960–5.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tennant DA, Duran RV, Boulahbel H, Gottlieb E. Metabolic transformation in cancer. Carcinogenesis. 2009;30(8):1269–80.CrossRefPubMedGoogle Scholar
  31. 31.
    Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011;13(5):589–98.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Priault M, Salin B, Schaeffer J, Vallette FM, di Rago JP, Martinou JC. Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ. 2005;12(12):1613–21.CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang DX, Gutterman DD. Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol. 2007;292(5):19.Google Scholar
  34. 34.
    Moungjaroen J, Nimmannit U, Callery PS, Wang L, Azad N, Lipipun V, et al. Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation. J Pharmacol Exp Ther. 2006;319(3):1062–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Schumacker PT. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell. 2006;10(3):175–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12(5):913–22.CrossRefPubMedGoogle Scholar
  37. 37.
    Tu HC, Ren D, Wang GX, Chen DY, Westergard TD, Kim H, et al. The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage. Proc Natl Acad Sci U S A. 2009;106(4):1093–8.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Fu D, Jordan JJ, Samson LD. Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis. Genes Dev. 2013;27(10):1089–100.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Cheng WH, Wu RT, Wu M, Rocourt CR, Carrillo JA, Song J, et al. Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death. Biochem Biophys Res Commun. 2012;420(1):24–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Circu ML, Aw TY. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med. 2010;48(6):749–62.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Srivastava DK, Berg BJ, Prasad R, Molina JT, Beard WA, Tomkinson AE, et al. Mammalian abasic site base excision repair. Identification of the reaction sequence and rate-determining steps. J Biol Chem. 1998;273(33):21203–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Liu Y, Prasad R, Beard WA, Kedar PS, Hou EW, Shock DD, et al. Coordination of steps in single-nucleotide base excision repair mediated by apurinic/apyrimidinic endonuclease 1 and DNA polymerase beta. J Biol Chem. 2007;282(18):13532–41.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Matsumoto Y, Kim K. Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair. Science. 1995;269(5224):699–702.CrossRefPubMedGoogle Scholar
  44. 44.
    Chaitanya GV, Steven AJ, Babu PP. PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun Signal. 2010;8(31):8–31.Google Scholar
  45. 45.
    Balunas MJ, Kinghorn AD. Drug discovery from medicinal plants. Life Sci. 2005;78(5):431–41.CrossRefPubMedGoogle Scholar
  46. 46.
    Liu XS, Jiang J, Jiao XY, Wu YE, Lin JH, Cai YM. Lycorine induces apoptosis and down-regulation of Mcl-1 in human leukemia cells. Cancer Lett. 2009;274(1):16–24.CrossRefPubMedGoogle Scholar
  47. 47.
    Lamoral-Theys D, Andolfi A, Van Goietsenoven G, Cimmino A, Le Calve B, Wauthoz N, et al. Lycorine, the main phenanthridine amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight. J Med Chem. 2009;52(20):6244–56.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Li Y, Liu J, Tang LJ, Shi YW, Ren W, Hu WX. Apoptosis induced by lycorine in KM3 cells is associated with the G0/G1 cell cycle arrest. Oncol Rep. 2007;17(2):377–84.PubMedGoogle Scholar
  49. 49.
    Liu J, Hu JL, Shi BW, He Y, Hu WX. Up-regulation of p21 and TNF-alpha is mediated in lycorine-induced death of HL-60 cells. Cancer Cell Int. 2010;10(25):1475–2867.Google Scholar
  50. 50.
    Li L, Dai HJ, Ye M, Wang SL, Xiao XJ, Zheng J, et al. Lycorine induces cell-cycle arrest in the G0/G1 phase in K562 cells via HDAC inhibition. Cancer Cell Int. 2012;12(1):1475–2867.Google Scholar
  51. 51.
    Liu J, Li Y, Tang LJ, Zhang GP, Hu WX. Treatment of lycorine on SCID mice model with human APL cells. Biomed Pharmacother. 2007;61(4):229–34.CrossRefPubMedGoogle Scholar
  52. 52.
    Gartel AL, Radhakrishnan SK. Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Res. 2005;65(10):3980–5.CrossRefPubMedGoogle Scholar
  53. 53.
    Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene. 2009;28(33):2925–39.CrossRefPubMedGoogle Scholar
  54. 54.
    Liu J, Hu WX, He LF, Ye M, Li Y. Effects of lycorine on HL-60 cells via arresting cell cycle and inducing apoptosis. FEBS Lett. 2004;578(3):245–50.CrossRefPubMedGoogle Scholar
  55. 55.
    Rasul A, Di J, Millimouno FM, Malhi M, Tsuji I, Ali M, et al. Reactive oxygen species mediate isoalantolactone-induced apoptosis in human prostate cancer cells. Molecules. 2013;18(8):9382–96.CrossRefPubMedGoogle Scholar
  56. 56.
    Tan C, Qian X, Jia R, Wu M, Liang Z. Matrine induction of reactive oxygen species activates p38 leading to caspase-dependent cell apoptosis in non-small cell lung cancer cells. Oncol Rep. 2013;30(5):2529–35.PubMedGoogle Scholar
  57. 57.
    Yang JT, Li ZL, Wu JY, Lu FJ, Chen CH. An oxidative stress mechanism of shikonin in human glioma cells. PLoS One. 2014;9(4).Google Scholar
  58. 58.
    Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 2009;8(7):579–91.CrossRefPubMedGoogle Scholar
  59. 59.
    Maillet A, Yadav S, Loo YL, Sachaphibulkij K, Pervaiz S. A novel Osmium-based compound targets the mitochondria and triggers ROS-dependent apoptosis in colon carcinoma. Cell Death Dis. 2013;6(4):185.Google Scholar
  60. 60.
    Bey EA, Bentle MS, Reinicke KE, Dong Y, Yang CR, Girard L, et al. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci U S A. 2007;104(28):11832–7.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Goldin N, Heyfets A, Reischer D, Flescher E. Mitochondria-mediated ATP depletion by anti-cancer agents of the jasmonate family. J Bioenerg Biomembr. 2007;39(1):51–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Swindall AF, Stanley JA, Yang ES. PARP-1: friend or foe of DNA damage and repair in tumorigenesis. Cancers. 2013;5(3):943–58.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Temkin V, Huang Q, Liu H, Osada H, Pope RM. Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis. Mol Cell Biol. 2006;26(6):2215–25.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ouyang Z, Zhu S, Jin J, Li J, Qiu Y, Huang M, et al. Necroptosis contributes to the cyclosporin A-induced cytotoxicity in NRK-52E cells. Pharmazie. 2012;67(8):725–32.PubMedGoogle Scholar
  66. 66.
    Jog NR, Caricchio R. Differential regulation of cell death programs in males and females by poly(ADP-ribose) polymerase-1 and 17beta estradiol. Cell Death Dis. 2013;8(4):251.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Yuhao Luo
    • 1
  • Mridul Roy
    • 1
  • Xiaojuan Xiao
    • 1
  • Shuming Sun
    • 1
  • Long Liang
    • 1
  • Huiyong Chen
    • 1
  • Yin Fu
    • 1
  • Yang Sun
    • 2
  • Min Zhu
    • 1
  • Mao Ye
    • 2
  • Jing Liu
    • 1
  1. 1.The State Key Laboratory of Medical Genetics & School of Life SciencesCentral South UniversityChangshaChina
  2. 2.Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical EngineeringHunan UniversityChangshaChina

Personalised recommendations