Investigational New Drugs

, Volume 28, Issue 3, pp 205–215 | Cite as

Augmented antitumor effects of combination therapy of cisplatin with ethaselen as a novel thioredoxin reductase inhibitor on human A549 cell in vivo

  • Qiang Tan
  • Jing Li
  • Han-wei Yin
  • Li-hui Wang
  • Wan-chen Tang
  • Fang Zhao
  • Xin-min Liu
  • Hui-hui Zeng


Ethaselen (1, 2-[bis (1, 2-Benzisoselenazolone-3 (2H) -ketone)] ethane, BBSKE), as a novel organoselenium compound targeting thioredoxin reductase (TrxR), has been reported to inhibit tumor growth and TrxR activity in several human tumor cell lines. It has now entered Phase I clinical trails. Here we report the effects of ethaselen and cisplatin (cis-diamminedichloroplatinum II, DDP) combination therapy (ethaselen 36 mg/kg, i.g., o.d. × 10 d and cisplatin 1 mg/kg, i.p., single at day 0) on human A549-grafted nude mouse model (female, BALB/c nude mouse, n = 5, treatment after tumor volume reached 100 mm3). Compared to single drug administration (either ethaselen: 36 mg/kg, i.g., o.d. × 10 d or cisplatin: 1.0 mg/kg, i.p., single at day 0), the combination therapy showed significantly reduced tumor size (presumably due to a synergistic effect) and no obvious toxic damage (both in terms of body weight maintenance and liver/kidney damage). These results will be significant in the development of novel anti-tumoral therapeutic strategies directed to non-small cell lung cancer (NSCLC).


Ethaselen Thioredoxin reductase inhibitor Cisplatin Non-small cell lung cancer Combination chemotherapy Synergistic effect 


Ethaselen (BBSKE)

1, 2-[bis (1,2-Benzisoselenazolone-3 (2H) -ketone)]ethane


Blood urea nitrogen




Hematoxylin eosin








No-observed adverse effect level


Non-small cell lung cancer


Specific pathogen free




Thioredoxin reductase



This work was supported in part by the National Natural Science Foundation of China (30472036).


  1. 1.
    Karin A (2006) Mammalian thioredoxin reductase as a drug target in anticancer therapy through direct apoptosis induction by selenium compromised forms of the protein. Karolinska University Press, SwedenGoogle Scholar
  2. 2.
    Powis G, Mustacich D, Coon A (2000) The role of the redox protein thioredoxin in cell growth and cancer. Free Radic Biol Med 29(3-4):312–322 doi: 10.1016/S0891-5849(00)00313-0 CrossRefPubMedGoogle Scholar
  3. 3.
    Powis G, Kirkpatrick DL (2007) Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol 7(4):392–397 doi: 10.1016/j.coph.2007.04.003 CrossRefPubMedGoogle Scholar
  4. 4.
    Selenius M, Fernandes AP, Brodin O, Björnstedt M, Rundlöf AK (2008) Treatment of lung cancer cells with cytotoxic levels of sodium selenite: Effects on the thioredoxin system. Biochem Pharmacol 75(11):2092–2099 doi: 10.1016/j.bcp.2008.02.028 CrossRefPubMedGoogle Scholar
  5. 5.
    Urig S, Becker K (2006) On the potential of thioredoxin reductase inhibitors for cancer therapy. Semin Cancer Biol 16(6):452–465 doi: 10.1016/j.semcancer.2006.09.004 CrossRefPubMedGoogle Scholar
  6. 6.
    Magda D, Miller RA (2006) Motexafin gadolinium: A novel redox active drug for cancer therapy. Semin Cancer Biol 16(6):466–476 doi: 10.1016/j.semcancer.2006.09.002 CrossRefPubMedGoogle Scholar
  7. 7.
    Lu J, Papp LV, Fang J, Rodriguez-Nieto S, Zhivotovsky B, Holmgren A (2006) Inhibition of mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity. Cancer Res 66(8):4410–4418 doi: 10.1158/0008-5472.CAN-05-3310 CrossRefPubMedGoogle Scholar
  8. 8.
    Zhao F, Yan J, Deng SJ, Lan LX, He F, Kuang B, Zeng HH (2006) A thioredoxin reductase inhibitor induces growth inhibition and apoptosis in five cultured human carcinoma cell lines. Cancer Lett 236(1):46–53 doi: 10.1016/j.canlet.2005.05.010 CrossRefPubMedGoogle Scholar
  9. 9.
    Shi CJ, Yu LZ, Yang FG, Yan J, Zeng HH (2003) A novel organoselenium compound induces cell cycle arrest and apoptosis in prostate cancer cell lines. Biochem Biophys Res Commun 309(3):578–583 doi: 10.1016/j.bbrc.2003.08.032 CrossRefPubMedGoogle Scholar
  10. 10.
    Peng ZF, Lan LX, Zhao F, Li J, Tan Q, Yin HW, Zeng HH (2008) A novel thioredoxin reductase inhibitor inhibits cell growth and induces apoptosis in HL-60 and K562 cells. J Zhejiang Univ Sci B 9(1):16–21 doi: 10.1631/jzus.B071605 CrossRefPubMedGoogle Scholar
  11. 11.
    Deng SJ, Kuang B, Zhou X, Yan J, Zhao F, Jia XY, Zeng HH (2003) BBSKE, 1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]ethane, induced cell death in tumor cells. Beijing Da Xue Xue Bao 35(1):108–109Google Scholar
  12. 12.
    Wang YR, Xiao JJ, Dong XM, Meng SC, Deng SJ, Kuang B, Yan J, Zhao F, Zeng HH (2005) The antitumor activity of Shuang-Xi-Zuo-Wan-1 in C57/BL mice. Beijing Da Xue Xue Bao 37(4):421–424PubMedGoogle Scholar
  13. 13.
    Xing FX, Li S, Ge X, Wang C, Zeng HH, Li D, Dong L (2008) The inhibitory effect of a novel organoselenium compound BBSKE on the tongue cancer Tca8113 in vitro and in vivo. Oral Oncol 44(10):963–969 doi: 10.1016/j.oraloncology.2007.12.001 CrossRefPubMedGoogle Scholar
  14. 14.
    Wang YR, Xiao JJ, Dong XM, Meng SC, Deng SJ, Kuang B, Yan J, Zhao F, Zeng HH (2006) Immune regulating activity of a novel organoselenium compound ethaselen-1 in C57 /BL mice. Beijing Da Xue Xue Bao 38(6):634–639PubMedGoogle Scholar
  15. 15.
    Lan LX, Zhao F, Wang Y, Zeng HH (2007) The mechanism of apoptosis induced by a novel thioredoxin reductase inhibitor in A549 cells: possible involvement of nuclear factor-κB- dependent pathway. Eur J Pharmacol 555(2-3):83–92 doi: 10.1016/j.ejphar.2006.10.037 CrossRefPubMedGoogle Scholar
  16. 16.
    Ho YP, Au-Yeung SC, To KK (2003) Platinum-based anticancer agents: innovative design strategies and biological perspectives. Med Res Rev 23(5):633–655 doi: 10.1002/med.10038 CrossRefPubMedGoogle Scholar
  17. 17.
    Momekov G, Bakalova A, Karaivanova M (2005) Novel approaches towards development of non-classical platinum-based antineoplastic agents: design of platinum complexes characterized by an alternative DNA-binding pattern and/or tumor-targeted cytotoxicity. Curr Med Chem 12(19):2177–2191 doi: 10.2174/0929867054864877 CrossRefPubMedGoogle Scholar
  18. 18.
    Loehrer PJ, Einhorn LH (1984) Drugs five years later. Cisplatin. Ann Intern Med 100(5):704–713Google Scholar
  19. 19.
    Sasada T, Nakamura H, Ueda S, Sato N, Kitaoka Y, Gon Y, Takabayashi A, Spyrou G, Holmgren A, Yodoi J (1999) Possible involvement of thioredoxin reductase as well as thioredoxin in cellular sensitivity to cis-diamminedichloroplatinum(II). Free Radic Biol Med 27(5-6):504–514 doi: 10.1016/S0891-5849(99)00101-X CrossRefPubMedGoogle Scholar
  20. 20.
    Lee SI, Brown MK, Eastman A (1999) Comparison of the efficacy of 7-Hydroxystaurosporine (UCN-01) and other staurosporine analogs to abrogate cisplatin-induced cell cycle arrest in human breast cancer cell lines. Biochem Pharmacol 58(11):1713–1721 doi: 10.1016/S0006-2952(99)00258-0 CrossRefPubMedGoogle Scholar
  21. 21.
    Egorin MJ, Moschel RC, Dolan ME (2005) Effect of cell cycle inhibition on cisplatin-induced cytotoxicity. J Pharmacol Exp Ther 312(1):206–213PubMedGoogle Scholar
  22. 22.
    Crescenzi E, Chiaviello A, Canti G, Reddi E, Veneziani BM, Palumbo G (2006) Low doses of cisplatin or gemcitabine plus Photofrin/photodynamic therapy: Disjointed cell cycle phase related activity accounts for synergistic outcome in metastatic non-small cell lung cancer cells (H1299). Mol Cancer Ther 5(3):776–785 doi: 10.1158/1535-7163.MCT-05-0425 CrossRefPubMedGoogle Scholar
  23. 23.
    Baldew GS, McVie JG, van der Valk MA, Los G, de Goeij JJ, Vermeulen NP (1990) Selective reduction of cis-Diamminedichloroplatinum (II) nephrotoxicity by Ebselen. Cancer Res 50(21):7031–7036PubMedGoogle Scholar
  24. 24.
    Aung HH, Mehendale SR, Wang CZ, Xie JT, McEntee E, Yuan CS (2007) Cisplatin’s tumoricidal effect on human breast carcinoma MCF-7 cells was not attenuated by American ginseng. Cancer Chemother Pharmacol 59(3):369–374 doi: 10.1007/s00280-006-0278-6 CrossRefPubMedGoogle Scholar
  25. 25.
    Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58(3):621–681 doi: 10.1124/pr.58.3.10 CrossRefPubMedGoogle Scholar
  26. 26.
    Miyake H, Tolcher A, Gleave ME (1999) Antisense Bcl-2 oligodeoxynucleotides inhibit progression to androgen-independence after castration in the Shionogi tumor model. Cancer Res 59(16):4030–4034PubMedGoogle Scholar
  27. 27.
    Holmgren A, Bjornstedt M (1995) Thioredoxin and thioredoxin reductase. Methods Enzymol 252(1):199–208 doi: 10.1016/0076-6879(95)52023-6 CrossRefPubMedGoogle Scholar
  28. 28.
    Smith AD, Guidry CA, Morris VC, Levander OA (1999) Aurothioglucose inhibits murine thioredoxin reductase activity in vivo. J Nutr 129(1):194–198PubMedGoogle Scholar
  29. 29.
    Placer ZA, Cushman LL, Johnson BC (1966) Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 16(2):359–364 doi: 10.1016/0003-2697(66)90167-9 CrossRefPubMedGoogle Scholar
  30. 30.
    Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 71(4):952–958 doi: 10.1016/0006-291X(76)90747-6 CrossRefPubMedGoogle Scholar
  31. 31.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108 doi: 10.3322/canjclin.55.2.74 CrossRefPubMedGoogle Scholar
  32. 32.
    Kiernan PD, Graling PR, Hetrick VL, Vaughan BE, Sheridan MJ, Lee JK (2004) A pragmatic and successful approach to treating non small-cell lung carcinoma. AORN J 80(5):840–857 doi: 10.1016/S0001-2092(06)60507-3 CrossRefPubMedGoogle Scholar
  33. 33.
    Gajra A, Newman N, Gamble GP, Abraham NZ, Kohman LJ, Graziano SL (2003) Impact of tumor size on survival in stage IA non-small cell lung cancer: a case for subdividing stage IA disease. Lung Cancer 42(1):51–57 doi: 10.1016/S0169-5002(03)00285-X CrossRefPubMedGoogle Scholar
  34. 34.
    Parkin DM, Bray FI, Devessa SS (2001) Cancer burden for the year 2000: the global picture. Eur J Cancer 37(suppl 8):64–66 doi: 10.1016/S0959-8049(01)00267-2 Google Scholar
  35. 35.
    Sun ZF, Yang P, Singh T, Dhindsa J, Larsen JE, Fong KM, Hayward NK, Potti A, Harpole DH Jr, Nevins JR (2007) Refining prognosis in non-small-cell lung cancer. N Engl J Med 356(2):189–191 doi: 10.1056/NEJMc062409 CrossRefPubMedGoogle Scholar
  36. 36.
    Non-small Cell Lung Cancer Collaborative Group (1995) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311(7010):899–908Google Scholar
  37. 37.
    Bearz A, Garassino I, Cavina R, Favaretto A, Boccalon M, Talamini R, Berretta M, Spazzapan S, Simonelli C, Santoro A, Tirelli U (2008) Pemetrexed single agent in previously treated non-small cell lung cancer: a multi-institutional observational study. Lung Cancer 60(2):240–245 doi: 10.1016/j.lungcan.2007.10.008 CrossRefPubMedGoogle Scholar
  38. 38.
    Weijl NI, Cleton FJ, Osanto S (1997) Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev 23(4):209–240 doi: 10.1016/S0305-7372(97)90012-8 CrossRefPubMedGoogle Scholar
  39. 39.
    Chu G (1994) Cellular responses to cisplatin: The roles of DNA binding proteins and DNA repair. J Biol Chem 269(2):787–790PubMedGoogle Scholar
  40. 40.
    Chou TC, Talalay P (1984) Quantitative analysis of dose effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55 doi: 10.1016/0065-2571(84)90007-4 CrossRefPubMedGoogle Scholar
  41. 41.
    Naziroglu M, Karaoğlu A, Aksoy AO (2004) Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology 195(2-3):221–230 doi: 10.1016/j.tox.2003.10.012 CrossRefPubMedGoogle Scholar
  42. 42.
    Soini Y, Kahlos K, Näpänkangas U, Kaarteenaho-Wiik R, Säily M, Koistinen P, Pääakkö P, Holmgren A, Kinnula VL (2001) Widespread Expression of thioredoxin and thioredoxin reductase in non-small cell lung carcinoma. Clin Cancer Res 7(6):1750–1757PubMedGoogle Scholar
  43. 43.
    Arner ES, Nakamura H, Sasada T, Yodoi J, Holmgren A, Spyrou G (2001) Analysis of the inhibition of mammalian thioredoxin, thioredoxin reductase, and glutaredoxin by cis-diamminedichloroplatinum(II) and its major metabolite, the glutathione-platinum complex. Free Radic Biol Med 31(10):1170–1178 doi: 10.1016/S0891-5849(01)00698-0 CrossRefPubMedGoogle Scholar
  44. 44.
    Su YT, Chang HL, Shyue SK, Hsu SL (2005) Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway. Biochem Pharmacol 70(2):229–241 doi: 10.1016/j.bcp.2005.04.026 CrossRefPubMedGoogle Scholar
  45. 45.
    Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281(5381):1309–1312 doi: 10.1126/science.281.5381.1309 CrossRefPubMedGoogle Scholar
  46. 46.
    Garcon G, Zerimech F, Hannothiaux M, Gosset P, Martin A, Marez T, Shirali P (2001) Antioxidant defense disruption by polycyclic aromatic hydrocarbons-coated onto Fe2O3 particles in human lung cells (A549). Toxicology 166(3):129–137 doi: 10.1016/S0300-483X(01)00461-9 CrossRefPubMedGoogle Scholar
  47. 47.
    Haendeler J, Zeiher AM, Dimmeler S (1996) Vitamin C and E prevent lipopolysaccharide- induced apoptosis in human endothelial cells by modulation of Bcl-2 and Bax. Eur J Pharmacol 317(2-3):407–411 doi: 10.1016/S0014-2999(96)00759-5 CrossRefPubMedGoogle Scholar
  48. 48.
    Vera G, Chiarlone A, Martin MI, Abalo R (2006) Altered feeding behaviour induced by long-term cisplatin in rats. Auton Neurosci 126-127:81–92 doi: 10.1016/j.autneu.2006.02.011 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Qiang Tan
    • 1
    • 2
  • Jing Li
    • 1
  • Han-wei Yin
    • 3
  • Li-hui Wang
    • 1
  • Wan-chen Tang
    • 1
  • Fang Zhao
    • 1
  • Xin-min Liu
    • 2
  • Hui-hui Zeng
    • 1
    • 4
  1. 1.State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical SciencesPeking UniversityBeijingChina
  2. 2.Peking University First HospitalBeijingChina
  3. 3.College of Life SciencesPeking UniversityBeijingChina
  4. 4.School of Pharmaceutical SciencesPeking University Health Science CenterBeijingChina

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