Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 387, Issue 9, pp 799–809 | Cite as

Menadione induces the formation of reactive oxygen species and depletion of GSH-mediated apoptosis and inhibits the FAK-mediated cell invasion

  • Yun Jeong Kim
  • Yong Kyoo Shin
  • Dong Suep Sohn
  • Chung Soo LeeEmail author
Original Article


Menadione induces apoptosis in tumor cells. However, the mechanism of apoptosis in ovarian cancer cells exposed to menadione is not clear. In addition, it is unclear whether menadione-induced apoptosis is mediated by the depletion of glutathione (GSH) contents that is associated with the formation of reactive oxygen species. Furthermore, the effect of menadione on the invasion and migration of human epithelial ovarian cancer cells has not been studied. Therefore, we investigated the effects of menadione exposure on apoptosis, cell adhesion, and cell migration using the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. The results suggest that menadione may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of menadione appears to be mediated by the formation of reactive oxygen species and the depletion of GSH. Menadione inhibited fetal-bovine-serum-induced cell adhesion and migration of OVCAR-3 cells, possibly through the suppression the focal adhesion kinase (FAK)-dependent activation of cytoskeletal-associated components. Therefore, menadione might be beneficial in the treatment of epithelial ovarian adenocarcinoma and combination therapy.


Menadione Epithelial ovarian adenocarcinoma cell lines Apoptosis-related proteins Cell adhesion and migration 



This study was supported by grant of the BK21plus Skin Barrier Network Human Resources Development Team, National Research Foundation of Korea, Ministry of Education.


  1. Akiyoshi T, Matzno S, Sakai M, Okamura N, Matsuyama K (2009) The potential of vitamin K3 as an anticancer agent against breast cancer that acts via the mitochondria-related apoptotic pathway. Cancer Chemother Pharmacol 65:143–150PubMedCrossRefGoogle Scholar
  2. Armstrong JS (2006) Mitochondria: a target for cancer therapy. Br J Pharmacol 147:239–248PubMedCentralPubMedGoogle Scholar
  3. Baumgartner HK, Gerasimenko JV, Thorne C, Ashurst LH, Barrow SL, Chvanov MA, Gillies S, Criddle DN, Tepikin AV, Petersen OH, Sutton R, Watson AJ, Gerasimenko OV (2007) Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins. Am J Physiol Gastrointest Liver Physiol 293:G296–G307PubMedGoogle Scholar
  4. Berthier A, Lemaire-Ewing S, Prunet C, Monier S, Athias A, Bessede G, Pais de Barros JP, Laubriet A, Gambert P, Lizard G, Néel D (2004) Involvement of a calcium-dependent dephosphorylation of BAD associated with the localization of Trpc-1 within lipid rafts in 7-ketocholesterol-induced THP-1 cell apoptosis. Cell Death Differ 11:897–905PubMedCrossRefGoogle Scholar
  5. Borutaite V (2010) Mitochondria as decision-makers in cell death. Environ Mol Mutagen 51:406–416PubMedGoogle Scholar
  6. Camins A, Pallas M, Silvestre JS (2008) Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches. Methods Find Exp Clin Pharmacol 30:43–65PubMedCrossRefGoogle Scholar
  7. Chen F, Wang W, El-Deiry WS (2010) Current strategies to target p53 in cancer. Biochem Pharmacol 80:724–730PubMedCrossRefGoogle Scholar
  8. Chen MF, Yang CM, Su CM, Liao JW, Hu ML (2011) Inhibitory effect of vitamin C in combination with vitamin K3 on tumor growth and metastasis of Lewis lung carcinoma xenografted in C57BL/6 mice. Nutr Cancer 63:1036–1043PubMedCrossRefGoogle Scholar
  9. Chipuk JE, Green DR (2006) Dissecting p53-dependent apoptosis. Cell Death Differ 13:994–1002PubMedCrossRefGoogle Scholar
  10. Chon HS, Hu W, Kavanagh JJ (2006) Targeted therapies in gynecologic cancers. Curr Cancer Drug Targets 6:333–363PubMedCrossRefGoogle Scholar
  11. Circu ML, Aw TY (2008) Glutathione and apoptosis. Free Radic Res 42:689–706PubMedCentralPubMedCrossRefGoogle Scholar
  12. Dai Y, Liu M, Tang W, Li Y, Lian J, Lawrence TS, Xu L (2009) A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-κB. BMC Cancer 9:392PubMedCentralPubMedCrossRefGoogle Scholar
  13. Dias N, Bailly C (2005) Drugs targeting mitochondrial functions to control tumor cell growth. Biochem Pharmacol 70:1–12Google Scholar
  14. Dunning S, Hannivoort RA, de Boer JF, Buist-Homan M, Faber KN, Moshage H (2009) Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death. Liver Int 29:922–932PubMedCrossRefGoogle Scholar
  15. Franco R, Cidlowski JA (2006) SLCO/OATP-like transport of glutathione in FasL-induced apoptosis: glutathione efflux is coupled to an organic anion exchange and is necessary for the progression of the execution phase of apoptosis. J Biol Chem 281:29542–29557PubMedCrossRefGoogle Scholar
  16. Franco R, Cidlowski JA (2009) Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ 16:1303–1314PubMedCrossRefGoogle Scholar
  17. Fu W, Luo H, Parthasarathy S, Mattson MP (1998) Catecholamines potentiate amyloid β-peptide neurotoxicity: involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis. Neurobiol Dis 5:229–243PubMedCrossRefGoogle Scholar
  18. Hitomi M, Yokoyama F, Kita Y, Nonomura T, Masaki T, Yoshiji H, Inoue H, Kinekawa F, Kurokohchi K, Uchida N, Watanabe S, Kuriyama S (2005) Antitumor effects of vitamins K1, K2 and K3 on hepatocellular carcinoma in vitro and in vivo. Int J Oncol 26:713–720PubMedGoogle Scholar
  19. Holmes K, Roberts OL, Thomas AM, Cross MJ (2007) Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 19:2003–2012PubMedCrossRefGoogle Scholar
  20. Hu W, Kavanagh JJ (2003) Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 4:721–729PubMedCrossRefGoogle Scholar
  21. Jin Z, El-Deiry WS (2005) Overview of cell death signaling pathways. Cancer Biol Ther 4:139–163PubMedCrossRefGoogle Scholar
  22. Kim R, Emi M, Tanabe K (2006) Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 57:545–553PubMedCrossRefGoogle Scholar
  23. Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J J437:169–183CrossRefGoogle Scholar
  24. Kohno M, Tanimura S, Ozaki K (2011) Targeting the extracellular signal-regulated kinase pathway in cancer therapy. Biol Pharm Bull 34:1781–1784Google Scholar
  25. Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84:359–369PubMedCrossRefGoogle Scholar
  26. Loor G, Kondapalli J, Schriewer JM, Chandel NS, Vanden Hoek TL, Schumacker PT (2010) Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis. Free Radic Biol Med 49:1925–1936PubMedCentralPubMedCrossRefGoogle Scholar
  27. Markman B, Dienstmann R, Tabernero J (2010) Targeting the PI3K/Akt/mTOR pathway-beyond rapalogs. Oncotarget 1:530–543Google Scholar
  28. Masson-Gadais B, Houle F, Laferriere J, Huot J (2003) Integrin avh3, requirement for VEGFR2-mediated activation of SAPK2/p38 and for Hsp90-dependent phosphorylation of focal adhesion kinase in endothelial cells activated by VEGF. Cell Stress Chaperones 8:37–52PubMedCentralPubMedCrossRefGoogle Scholar
  29. Mignotte B, Vayssière JL (1998) Mitochondria and apoptosis. Eur J Biochem 252:1–15PubMedCrossRefGoogle Scholar
  30. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63PubMedCrossRefGoogle Scholar
  31. Ogawa M, Nakai S, Deguchi A, Nonomura T, Masaki T, Uchida N, Yoshiji H, Kuriyama S (2007) Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells. Int J Oncol 31:323–331PubMedGoogle Scholar
  32. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922PubMedCrossRefGoogle Scholar
  33. van Klaveren RJ, Hoet PHM, Pype JL, Demedts M, Nemery B (1997) Increase in gamma-glutamyltransferase by glutathione depletion in rat type II pneumocytes. Free Radic Biol Med 22:525–534Google Scholar
  34. van Nimwegen MJ, Verkoeijen S, van Buren L, Burg D, van de Water B (2005) Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation. Cancer Res 65:4698–4706PubMedCrossRefGoogle Scholar
  35. von Gruenigen VE, Jamison JM, Gilloteaux J, Lorimer HE, Summers M, Pollard RR, Gwin CA, Summers JL (2003) The in vitro antitumor activity of vitamins C and K3 against ovarian carcinoma. Anticancer Res 23:3279–3287Google Scholar
  36. Wu H, Rao GN, Dai B, Singh P (2000) Autocrinegastrins in colon cancer cells up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-8. J Biol Chem 275:32491–32498PubMedCrossRefGoogle Scholar
  37. Zhivotovsky B, Orrenius S (2010) Cell death mechanisms: cross-talk and role in disease. Exp Cell Res 316:1374–1383PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Yun Jeong Kim
    • 1
  • Yong Kyoo Shin
    • 1
  • Dong Suep Sohn
    • 2
  • Chung Soo Lee
    • 1
    Email author
  1. 1.Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development TeamChung-Ang UniversitySeoulSouth Korea
  2. 2.Department of Thoracic and Cardiovascular SurgeryChung-Ang University HospitalSeoulSouth Korea

Personalised recommendations