Ukr.Biochem.J. 2015; Volume 87, Issue 3, May-Jun, pp. 63-74


Inhibitor of the transcription factor NF-κB, DHMEQ, enhances the effect of paclitaxel on cells of anaplastic thyroid carcinoma in vitro and in vivo

V. V. Pushkarev1, D. V. Starenki2, V. M. Pushkarev1,
O. I. Kovzun1, M. D. Tronko1

1State Institution V. P. Komisarenko Institute of Endocrinology and Metabolism,
National Academy of Medical Sciences of Ukraine, Kyiv;
2Department of Biochemistry, Medical College of Wisconsin, USA;

Anticancer drug paclitaxel (Ptx) effect on biochemical mechanisms, regulating apoptosis in anaplastic thyroid carcinoma cells, was studied. It was shown that in addition to apoptotic cell death, Ptx induces signa­ling cascades that ensure cell survival. Paclitaxel-induced activation of nuclear factor kappa B (NF‑κВ) leads to an increase of some antiapoptotic proteins expression such as survivin, cIAP, XIAP. A novel NF‑κВ inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was found to enhance cytotoxic effect of Ptx in anaplastic thyroid carcinoma cells. An enhancement of caspase-3 and -9 activation and PARP cleavage as well as the decreased levels of proteins-inhibitors of apoptosis were observed when cells were treated with a combination of both drugs. Mitochondria transmembrane potential (ΔΨm) loss was observed at higher concentrations of Ptx and DHMEQ. NF-κВ inhibition also potentiates paclitaxel effect at tumors formed by xenotransplantation of FRO cells into mice. Tumor mass reduction, significantly different from the effects of each of the compounds alone, was observed in animals, treated with paclitaxel and  NF-κВ inhibitor. Thus, the combined use of paclitaxel and NF-κВ inhibitor inhibits biochemical processes that contribute to the resistance of anaplastic thyroid carcinoma cells to paclitaxel action.

Keywords: , , , ,


  1. Kingston DG. The shape of things to come: structural and synthetic studies of taxol and related compounds. Phytochemistry. 2007 Jul;68(14):1844-54. Review. PubMed, PubMedCentral
  2. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004 Apr;4(4):253-65. Review. PubMed, CrossRef
  3. Pushkarev VM, Starenki DV, Saenko VA, Namba H, Kurebayashi J, Tronko MD, Yamashita S. Molecular mechanisms of the effects of low concentrations of taxol in anaplastic thyroid cancer cells. Endocrinology. 2004 Jul;145(7):3143-52. PubMed, CrossRef
  4. Pushkarev VM, Starenki DV, Saenko VO, Tronko MD, Yamashita S. Effects of Paclitaxel and combination of the drug with radiation therapy in an in vivo model of anaplastic thyroid carcinoma. Exp Oncol. 2011 Mar;33(1):24-7. PubMed
  5. Ghosh S. Handbook of transcription factor NF-kappaB. LLC Boca Raton: CRC Press by Taylor & Francis Group, 2007; 223 р.
  6. Hayden MS, Ghosh S. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 2012 Feb 1;26(3):203-34. Review. PubMed, PubMedCentral, CrossRef
  7. Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a000141. Review. PubMed, PubMedCentral, CrossRef
  8. Chaturvedi MM, Sung B, Yadav VR, Kannappan R, Aggarwal BB. NF-κB addiction and its role in cancer: ‘one size does not fit all’. Oncogene. 2011 Apr 7;30(14):1615-30. Review. PubMed, PubMedCentral,  CrossRef
  9. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010 Mar 19;140(6):883-99. Review. PubMed, PubMedCentralCrossRef
  10. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010 Feb;21(1):11-9. Review. PubMed, PubMedCentral, CrossRef
  11. Nagel D, Vincendeau M, Eitelhuber AC, Krappmann D. Mechanisms and consequences of constitutive NF-κB activation in B-cell lymphoid malignancies. Oncogene. 2014 Dec 11;33(50):5655-65. Review. PubMed, CrossRef
  12. Altieri DC. Survivin and IAP proteins in cell-death mechanisms. Biochem J. 2010 Sep 1;430(2):199-205. Review. PubMed,  PubMedCentral, CrossRef
  13. Winsauer G, Resch U, Hofer-Warbinek R, Schichl YM, de Martin R. XIAP regulates bi-phasic NF-kappaB induction involving physical interaction and ubiquitination of MEKK2. Cell Signal. 2008 Nov;20(11):2107-12. PubMed, CrossRef
  14. Gyrd-Hansen M, Meier P. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer. 2010 Aug;10(8):561-74. Review. PubMed, CrossRef
  15. Pacifico F, Mauro C, Barone C, Crescenzi E, Mellone S, Monaco M, Chiappetta G, Terrazzano G, Liguoro D, Vito P, Consiglio E, Formisano S, Leonardi A. Oncogenic and anti-apoptotic activity of NF-kappa B in human thyroid carcinomas. J Biol Chem. 2004 Dec 24;279(52):54610-9. Epub 2004 Oct 8. PubMed, CrossRef
  16. Li F, Sethi G. Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. Biochim Biophys Acta. 2010 Apr;1805(2):167-80. Review. PubMed, CrossRef
  17. Starenki D, Namba H, Saenko V, Ohtsuru A, Yamashita S. Inhibition of nuclear factor-kappaB cascade potentiates the effect of a combination treatment of anaplastic thyroid cancer cells. J Clin Endocrinol Metab. 2004 Jan;89(1):410-8.  PubMed
  18. Scaduto RC Jr, Grotyohann LW. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J. 1999 Jan;76(1 Pt 1):469-77. PubMed, PubMedCentral, CrossRef
  19. Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, Lang JY, Lai CC, Chang CJ, Huang WC, Huang H, Kuo HP, Lee DF, Li LY, Lien HC, Cheng X, Chang KJ, Hsiao CD, Tsai FJ, Tsai CH, Sahin AA, Muller WJ, Mills GB, Yu D, Hortobagyi GN, Hung MC. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008 Feb;10(2):138-48.  PubMed, PubMedCentral, CrossRef
  20. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013 Mar;13(3):184-99. Review. PubMed, PubMedCentral, CrossRef
  21. Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, Moscat J. The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 2008 Apr;13(4):343-54. PubMed,  CrossRef
  22. Lawrence MC, Jivan A, Shao C, Duan L, Goad D, Zaganjor E, Osborne J, McGlynn K, Stippec S, Earnest S, Chen W, Cobb MH. The roles of MAPKs in disease. Cell Res. 2008 Apr;18(4):436-42. Review.  PubMed, CrossRef
  23. Luchnik AN. A model of self-maintenance of in vivo malignant growth not dependent on tumour type or origin: syndrome of everlasting wound healing. Cancer Biol Ther. 2003 Jul-Aug;2(4):343-6. Review. PubMed, CrossRef

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