Skip to main content

Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity

Apoptosis volume 11, pages 2225–2235 (2006)Cite this article

Abstract

The sesquiterpene lactone, parthenolide (PTL), possesses strong anticancer activity against various cancer cells. We report that PTL strongly induced apoptosis in 4 multiple myeloma (MM) cell lines and primary MM cells (CD38+ high), but barely induced death in normal lymphocytes (CD38−/+low). PTL-mediated apoptosis correlated well with ROS generation and was almost completely inhibited by L-N-acetylcysteine (L-NAC), indicating the crucial role of oxidative stress in the mechanism. Among 4 MM cell lines, there is considerable difference in susceptibility to PTL. KMM-1 and MM1S cells sensitive to PTL possess less catalase activity than the less sensitive KMS-5 and NCI-H929 cells as well as normal lymphocytes. A catalase inhibitor 3-amino-1,2,4-triazole enhanced their PTL-mediated ROS generation and cell death. The siRNA-mediated knockdown of catalase in KMS-5 cells decreased its activity and sensitized them to PTL. Our findings indicate that PTL induced apoptosis in MM cells depends on increased ROS and intracellular catalase activity is a crucial determinant of their sensitivity to PTL.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Knight DW (1995) Feverfew: chemistry and biological activity. Nat Prod Rep 12:271–76

    Article  CAS  PubMed  Google Scholar 

  2. Zhang S, Ong CN, Shen HM (2004) Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett 208:143–53

    Article  CAS  PubMed  Google Scholar 

  3. Woynarowski JM, Konopa J (1981) Inhibition of DNA biosynthesis in HeLa cells by cytotoxic and antitumor sesquiterpene lactones. Mol Pharmacol 19: 97–02

    PubMed  Google Scholar 

  4. Zhang S, Lin ZN, Yang CF, Shi X, Ong CN, Shen HM (2004) Suppressed NF-kappaB and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF-alpha-induced apoptosis in human cancer cells. Carcinogenesis 25:2191–199

    Article  CAS  PubMed  Google Scholar 

  5. Kwok BH, Koh B, Ndubuisi MI, Elofsson M, Crews CM (2001) The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem Biol 8:759–66

    Article  CAS  PubMed  Google Scholar 

  6. Hehner SP, Hofmann TG, Droge W, Schmitz ML (1999) The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. J Immunol 163:5617–623

    CAS  PubMed  Google Scholar 

  7. Garcia-Pineres AJ, Castro V, Mora G, Schmidt TJ, Strunck E, Pahl HL, Merfort I (2001) Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J Biol Chem 276:39713–9720

    Article  CAS  PubMed  Google Scholar 

  8. Sobota R, Szwed M, Kasza A, Bugno M, Kordula T (2000) Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family. Biochem Biophys Res Commun 267:329–33

    Article  CAS  PubMed  Google Scholar 

  9. Wen J, You KR, Lee SY, Song CH, Kim DG (2002) Oxidative stress-mediated apoptosis: the anticancer effect of the sesquiterpene lactone parthenolide. J Biol Chem 277:38954–8964

    Article  CAS  PubMed  Google Scholar 

  10. Nakshatri H, Rice SE, Bhat-Nakshatri P (2004) Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. Oncogene 23:7330–344

    Article  CAS  PubMed  Google Scholar 

  11. Kim JH, Liu L, Lee SO, Kim YT, You KR, Kim DG (2005) Susceptibility of cholangiocarcinoma cells to parthenolide-induced apoptosis. Cancer Res 65:6312–320

    Article  CAS  PubMed  Google Scholar 

  12. Yip-Schneider MT, Nakshatri H, Sweeney CJ, Marshall MS, Wiebke EA, Schmidt CM (2005) Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-kappa B pathway in pancreatic carcinoma cells. Mol Cancer Ther 4:587–94

    Article  CAS  PubMed  Google Scholar 

  13. Sweeney CJ, Mehrotra S, Sadaria MR, Kumar S, Shortle NH, Roman Y, Sheridan C, Campbell RA, Murry DJ, Badve S, Nakshatri H (2005) The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. Mol Cancer Ther 4:1004–012

    Article  CAS  PubMed  Google Scholar 

  14. Guzman ML, Rossi RM, Karnischky L, Karnischky L, Li X, Peterson DR, Howard DS, Jordan CT (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105:4163–139

    Article  CAS  PubMed  Google Scholar 

  15. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–617

    Article  CAS  PubMed  Google Scholar 

  16. Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C, Wu ZQ, Borad MJ, Frantzen M, Roussos E, Neeser J, Mikail A, Adams J, Sjak-Shie N, Vescio RA, Berenson JR. (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136–144

    Google Scholar 

  17. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B (1999) Antitumor activity of thalidomide in refractory multiple myeloma. New Engl J Med 341:1565–571

    Article  CAS  PubMed  Google Scholar 

  18. Keifer JA, Guttridge DC, Ashburner BP, Baldwin Jr AS (2001) Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity. J Biol Chem 276:22382–2387

    Article  CAS  PubMed  Google Scholar 

  19. Ling YH, Liebes L, Zou Y, Perez-Soler R (2003) Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem 278:33714–3723

    Article  CAS  PubMed  Google Scholar 

  20. Minami T, Adachi M, Kawamura R, Zhang Y, Shinomura Y, Imai K (2005) Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity. Clin Cancer Res 11:5248–256

    Article  CAS  PubMed  Google Scholar 

  21. Setsukinai K, Urano Y, Kakinuma K, Majima HJ, Nagano T (2003) Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J Biol Chem 278:3170–175

    Article  CAS  PubMed  Google Scholar 

  22. Begonja AJ, Gambaryan S, Geiger J, Aktas B, Pozgajova M, Nieswandt B, Walter U (2005) Platelet NAD(P)H-oxidase-generated ROS production regulates alphaIIbbeta3 -integrin activation independent of the NO/cGMP pathway. Blood 106:2757–760

    Article  CAS  PubMed  Google Scholar 

  23. Ambudkar SV, Sauna ZE, Gottesman MM, Szakacs G (2005) A novel way to spread drug resistance in tumor cells: functional intercellular transfer of P-glycoprotein (ABCB1). Trends Pharmacol Sci 26:385–87

    Article  CAS  PubMed  Google Scholar 

  24. Polgar O, Bates SE (2005) ABC transporters in the balance: is there a role in multidrug resistance? Biochem Soc Trans 33:241–45

    Article  CAS  PubMed  Google Scholar 

  25. Scandalios JG (2005) Oxidative stress: molecular perception and transduction of signals triggering antioxidant gene defenses. Braz J Med Biol Res 38:995–014

    Article  CAS  PubMed  Google Scholar 

  26. Chen X, Liang H, Van Remmen H, Vijg J, Richardson A (2004) Catalase transgenic mice: characterization and sensitivity to oxidative stress. Arch Biochem Biophys 422:197–10

    Article  CAS  PubMed  Google Scholar 

  27. Gupta R, Karpatkin S, Basch RS (2006) Hematopoiesis and stem cell renewal in long-term bone marrow cultures containing catalase. Blood. 107:1837–846

    Article  CAS  PubMed  Google Scholar 

  28. Bernal-Mizrachi L, Lovly CM, Ratner L (2006) The role of NF-kappaB-1 and NF-kappaB-2-mediated resistance to apoptosis in lymphomas. Proc Natl Acad Sci U S A 103:9220–225

    Article  CAS  PubMed  Google Scholar 

  29. Geiszt M, Leto TL (2004) NOX The Nox family of NAD(P)H oxidases: host defense and beyond. J Biol Chem 279:51715–1718

    Article  CAS  PubMed  Google Scholar 

  30. Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD (1999) Cell transformation by the superoxide- generating oxidase Mox1. Nature 401:79–2

    Article  CAS  PubMed  Google Scholar 

  31. Won YK, Ong CN, Shi X, Shen HM (2004) Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms. Carcinogenesis 25:1449–458

    Article  CAS  PubMed  Google Scholar 

  32. Ling YH, Liebes L, Zou Y, Perez-Soler R (2003) Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem 278:33714–3723

    Article  CAS  PubMed  Google Scholar 

  33. Fribley A, Zeng Q, Wang CY (2004) Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol 24:9695–704.

    Article  CAS  PubMed  Google Scholar 

  34. Perez-Galan P, Roue G, Villamor N, Montserrat E, Campo E, Colomer D (2006) The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood 107:257–64

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan

    Wei Wang, Masaaki Adachi, Rina Kawamura & Hiroki Sakamoto

  2. First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

    Masaaki Adachi, Toshiaki Hayashi, Tadao Ishida, Kohzoh Imai & Yasuhisa Shinomura

Authors
  1. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masaaki Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rina Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroki Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshiaki Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tadao Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kohzoh Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasuhisa Shinomura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masaaki Adachi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, W., Adachi, M., Kawamura, R. et al. Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity. Apoptosis 11, 2225–2235 (2006). https://doi.org/10.1007/s10495-006-0287-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-006-0287-2

Keywords

  • ROS
  • Parthenolide
  • Multiple myeloma
  • Catalase
  • NADPH oxidase