Synergistic effect of 17-allylamino-17-demethoxygeldanamycin with dehydroxymethylepoxyquinomicin on the human anaplastic thyroid carcinoma cell line KTC2

Authors

  • Lidija Todorović Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of thе Republic of Serbia, University of Belgrade, Belgrade http://orcid.org/0000-0003-0672-0693
  • Gorana Stamenković Department of Genetic Research, Institute for Biological Research “Siniša Stanković”, National Institute of thе Republic of Serbia, University of Belgrade, Belgrade https://orcid.org/0000-0002-5809-7189
  • Biljana Vučetić Tadić Institute for Mother and Child Healthcare of Serbia, Belgrade https://orcid.org/0000-0003-2245-8429
  • Kazuo Umezawa 1. Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki; 2. Department of Molecular Target Medicine, Aichi Medical University, Nagakute
  • Ana Božović Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of thе Republic of Serbia, University of Belgrade, Belgrade https://orcid.org/0000-0002-6487-6365
  • Shunichi Yamashita 1. Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki; 2. Fukushima Medical University, Fukushima https://orcid.org/0000-0001-6399-6261
  • Boban Stanojević 1. Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of thе Republic of Serbia, University of Belgrade, Belgrade; 2. Fukushima Medical University, Fukushima, Japan https://orcid.org/0000-0002-4674-0384

DOI:

https://doi.org/10.2298/ABS201010055T

Keywords:

NF-κB inhibitor, Hsp90 inhibitor, synergy, targeted inhibitor, combined treatment

Abstract

Paper description:

  • A treatment modality that combines two or more therapeutic agents is the cornerstone of cancer therapy.
  • Using combination-index/isobologram and Western analyses, the effect of the combined treatment of Hsp90 and NF-κB inhibitors, 17-allylamino-17-demethoxygeldanamycin and dehydroxymethylepoxyquinomicin respectively, on cancer cell growth and apoptosis in the anaplastic thyroid carcinoma cell line KTC2 was investigated.
  • Compared to single agent treatment, the combined treatment enhanced the growth-inhibitory effects in a synergistic manner and strongly potentiated apoptosis.
  • The combination of Hsp90 and NF-κB inhibitors is a more effective modality for inhibiting the proliferation/survival of KTC2 cells compared to either agent alone.

Abstract: The use of targeted inhibitors has shown promise as an effective approach in cancer therapy. However, targeted therapies based only on one drug, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), have limited success, partly because cancer cells engage alternate pathways for survival and proliferation. In the present study, we evaluated whether dehydroxymethylepoxyquinomicin (DHMEQ), a nuclear factor κB (NF-κB) inhibitor, can enhance the antitumor activities of 17-AAG, a 90 kDa heat shock protein (Hsp90) inhibitor, in the anaplastic thyroid cancer cell line KTC2. We examined the effect of combined drug treatment vs single drug treatment on cell survival. Isobologram analysis was performed to distinguish the additive vs synergistic effects of the drug combination. Western blotting was performed to investigate apoptosis markers: caspase 3, poly(ADP-ribose) polymerase-one (PARP-1), B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 2 (cIAP-2). Compared to monotherapy, the combined treatment enhanced growth-inhibitory effects in a synergistic manner and strongly potentiated apoptosis. These results demonstrate the first in vitro evidence that a combination of Hsp90 and NF-κB inhibitors is a more effective modality for inhibiting cell proliferation and survival in anaplastic thyroid carcinoma cells than either agent alone, warranting further investigations.

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References

Chintakuntlawar AV FR, Kasperbauer JL, Bible KC. Diagnosis and Management of Anaplastic Thyroid Cancer. Endocrinol Metab Clin North Am. 2019;48(1):269-84.

Shikha Saini KT, Ajay V Maker, Kenneth D Burman, Bellur S Prabhakar Therapeutic advances in anaplastic thyroid cancer: a current perspective. Mol Canc. 2018;17(1):154. https://doi.org/10.1186/s12943-018-0903-0

Pearl LH, Prodromou C, Workman P. The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem J. 2008;410(3):439-53. https://doi.org/10.1042/bj20071640

Workman P. Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett. 2004;206(2):149-57. https://doi.org/10.1016/j.canlet.2003.08.032

Chiosis G, Neckers L. Tumor selectivity of Hsp90 inhibitors: the explanation remains elusive. ACS Chem Biol. 2006;1(5):279-84. https://doi.org/10.1021/cb600224w

Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A. 1994;91(18):8324-8. https://doi.org/10.1073/pnas.91.18.8324

Hadden MK, Lubbers DJ, Blagg BS. Geldanamycin, radicicol, and chimeric inhibitors of the Hsp90 N-terminal ATP binding site. Curr Top Med Chem. 2006;6(11):1173-82. https://doi.org/10.2174/156802606777812031

Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003;425(6956):407-10. https://doi.org/10.1038/nature01913

Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol. 2011;7(11):818-26. https://doi.org/10.1038/nchembio.670

Kim SH, Kang JG, Kim CS, Ihm SH, Choi MG, Yoo HJ, Lee SJ. 17-Allylamino-17-demethoxygeldanamycin and Herbimycin A Induce Cell Death by Modulating beta-Catenin and PI3K/AKT Signaling in FRO Anaplastic Thyroid Carcinoma Cells. Anticancer Res. 2015;35(10):5453-60. https://doi.org/10.1007/s12020-014-0371-2

Kim SH, Kang JG, Kim CS, Ihm SH, Choi MG, Yoo HJ, Lee SJ. The effect of 17-allylamino-17-demethoxygeldanamycin alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells. Endocrine. 2015;48(3):886-93. https://doi.org/10.1007/s12020-014-0371-2

Braga-Basaria M, Hardy E, Gottfried R, Burman KD, Saji M, Ringel MD. 17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines correlates with heat shock protein 90 levels. J Clin Endocrinol Metab. 2004;89(6):2982-8. https://doi.org/10.1210/jc.2003-031767

White PT, Subramanian C, Zhu Q, Zhang H, Zhao H, Gallagher R, Timmermann BN, Blagg BS, Cohen MS. Novel HSP90 inhibitors effectively target functions of thyroid cancer stem cell preventing migration and invasion. Surgery. 2016;159(1):142-51. https://doi.org/10.1016/j.surg.2015.07.050

Talaei S, Mellatyar H, Asadi A, Akbarzadeh A, Sheervalilou R, Zarghami N. Spotlight on 17-AAG as an Hsp90 inhibitor for molecular targeted cancer treatment. Chem Biol Drug Des. 2019;93(5):760-86. https://doi.org/10.1111/cbdd.13486

Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 2010;1799(10-12):775-87. https://doi.org/10.1016/j.bbagrm.2010.05.004

Namba H, Saenko V, Yamashita S. Nuclear factor-kB in thyroid carcinogenesis and progression: a novel therapeutic target for advanced thyroid cancer. Arq Bras Endocrinol Metabol. 2007;51(5):843-51. https://doi.org/10.1590/s0004-27302007000500023

Pacifico F, Leonardi A. Role of NF-kappaB in thyroid cancer. Mol Cell Endocrinol. 2010;321(1):29-35.

Shiraiwa K, Matsuse M, Nakazawa Y, Ogi T, Suzuki K, Saenko V, Xu S, Umezawa K, Yamashita S, Tsukamoto K, Mitsutake N. JAK/STAT3 and NF-kappaB Signaling Pathways Regulate Cancer Stem-Cell Properties in Anaplastic Thyroid Cancer Cells. Thyroid. 2019;29(5):674-82. https://doi.org/10.1089/thy.2018.0212

Umezawa K, Chaicharoenpong C. Molecular design and biological activities of NF-kappaB inhibitors. Mol Cells. 2002;14(2):163-7.

Castro-Gamero AM, Borges KS, da Silva Silveira V, Lira RC, de Paula Gomes Queiroz R, Valera FC, Scrideli CA, Umezawa K, Tone LG. Inhibition of nuclear factor-kappaB by dehydroxymethylepoxyquinomicin induces schedule-dependent chemosensitivity to anticancer drugs and enhances chemoinduced apoptosis in osteosarcoma cells. Anticancer Drugs. 2012;23(6):638-50. https://doi.org/10.1097/cad.0b013e328350e835

Horiguchi Y, Kuroda K, Nakashima J, Murai M, Umezawa K. Antitumor effect of a novel nuclear factor-kappa B activation inhibitor in bladder cancer cells. Expert Rev Anticancer Ther. 2003;3(6):793-8. https://doi.org/10.1586/14737140.3.6.793

Nishimura D, Ishikawa H, Matsumoto K, Shibata H, Motoyoshi Y, Fukuta M, Kawashimo H, Goto T, Taura N, Ichikawa T, Hamasaki K, Nakao K, Umezawa K, Eguchi K. DHMEQ, a novel NF-kappaB inhibitor, induces apoptosis and cell-cycle arrest in human hepatoma cells. Int J Oncol. 2006;29(3):713-9. https://doi.org/10.3892/ijo.29.3.713

Starenki DV, Namba H, Saenko VA, Ohtsuru A, Maeda S, Umezawa K, Yamashita S. Induction of thyroid cancer cell apoptosis by a novel nuclear factor kappaB inhibitor, dehydroxymethylepoxyquinomicin. Clin Cancer Res. 2004;10(20):6821-9. https://doi.org/10.1158/1078-0432.ccr-04-0463

Kawabe Y, Eguchi K, Shimomura C, Mine M, Otsubo T, Ueki Y, Tezuka H, Nakao H, Kawakami A, Migita K, Yamashita S, Matsunga M, Ishikawa N, Ito K, Nagataki S. Interleukin-1 production and action in thyroid tissue. J Clinic Endocrinol Metabol. 1989;68(6):1174-83. https://doi.org/10.1210/jcem-68-6-1174

Chou TC TP. Analysis of combined drug effects: a new look at a very old problem. Trends Pharmacol Sci. 1983;4:450-54.

Liu D, Hou P, Liu Z, Wu G, Xing M. Genetic alterations in the phosphoinositide 3-kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycin. Cancer Res. 2009;69(18):7311-9. https://doi.org/10.1158/0008-5472.can-09-1077

Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nature Methods. 2012;9(7):671-75. https://doi.org/10.1038/nmeth.2089

Liu R, Blower PE, Pham AN, Fang J, Dai Z, Wise C, Green B, Teitel CH, Ning B, Ling W, Lyn-Cook BD, Kadlubar FF, Sadee W, Huang Y. Cystine-glutamate transporter SLC7A11 mediates resistance to geldanamycin but not to 17-(allylamino)-17-demethoxygeldanamycin. Mol Pharmacol. 2007;72(6):1637-46. https://doi.org/10.1124/mol.107.039644

Shrestha L, Bolaender A, Patel HJ, Taldone T. Heat Shock Protein (HSP) Drug Discovery and Development: Targeting Heat Shock Proteins in Disease. Curr Top Med Chem. 2016;16(25):2753-64. https://doi.org/10.2174/1568026616666160413141911

Xu Y, Zhu Q, Chen D, Shen Z, Wang W, Ning G, Zhu Y. The HSP90 inhibitor 17-AAG exhibits potent antitumor activity for pheochromocytoma in a xenograft model. Tumour Biol. 2015;36(7):5103-8. https://doi.org/10.1007/s13277-015-3162-3

Katsman A, Umezawa K, Bonavida B. Chemosensitization and immunosensitization of resistant cancer cells to apoptosis and inhibition of metastasis by the specific NF-kappaB inhibitor DHMEQ. Curr Pharm Des. 2009;15(7):792-808. https://doi.org/10.2174/138161209787582156

Heavey S, Godwin P, Baird AM, Barr MP, Umezawa K, Cuffe S, Finn SP, O'Byrne KJ, Gately K. Strategic targeting of the PI3K-NFkappaB axis in cisplatin-resistant NSCLC. Cancer Biol Ther. 2014;15(10):1367-77. https://doi.org/10.4161/cbt.29841

Ramos PMM, Pezuk JA, Castro-Gamero AM, Oliveira HF, Scrideli CA, Umezawa K, Tone LG. Antineoplastic Effects of NF-kappaB Inhibition by DHMEQ (Dehydroxymethylepoxyquinomicin) Alone and in Co-treatment with Radio-and Chemotherapy in Medulloblastoma Cell Lines. Anticancer Agents Med Chem. 2018;18(4):541-49. https://doi.org/10.2174/1871520617666171113151335

Ryan SL, Beard S, Barr MP, Umezawa K, Heavey S, Godwin P, Gray SG, Cormican D, Finn SP, Gately KA, Davies AM, Thompson EW, Richard DJ, O'Byrne KJ, Adams MN, Baird AM. Targeting NF-kappaB-mediated inflammatory pathways in cisplatin-resistant NSCLC. Lung Cancer. 2019;135:217-27. https://doi.org/10.1016/j.lungcan.2019.07.006

Pushkarev VV, Starenki DV, Pushkarev VM, Kovzun OI, Tronko MD. Inhibitor of the transcription factor NF-kappaB, DHMEQ, enhances the effect of paclitaxel on cells of anaplastic thyroid carcinoma in vitro and in vivo. Ukr Biochem J. 2015;87(3):63-74. https://doi.org/10.15407/ubj87.03.063

Meng Z, Mitsutake N, Nakashima M, Starenki D, Matsuse M, Takakura S, Namba H, Saenko V, Umezawa K, Ohtsuru A, Yamashita S. Dehydroxymethylepoxyquinomicin, a novel nuclear Factor-kappaB inhibitor, enhances antitumor activity of taxanes in anaplastic thyroid cancer cells. Endocrinology. 2008;149(11):5357-65. https://doi.org/10.1210/en.2008-0279

Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene. 1999;18(49):6910-24. https://doi.org/10.1038/sj.onc.1203238

Lampiasi N, Azzolina A, Umezawa K, Montalto G, McCubrey JA, Cervello M. The novel NF-kappaB inhibitor DHMEQ synergizes with celecoxib to exert antitumor effects on human liver cancer cells by a ROS-dependent mechanism. Cancer Lett. 2012;322(1):35-44. https://doi.org/10.1016/j.canlet.2012.02.008

Togano T, Nakashima M, Watanabe M, Umezawa K, Watanabe T, Higashihara M, Horie R. Synergistic effect of 5-azacytidine and NF-kappaB inhibitor DHMEQ on apoptosis induction in myeloid leukemia cells. Oncol Res. 2012;20(12):571-7. https://doi.org/10.3727/096504013x13775486749371

Brassesco MS, Roberto GM, Morales AG, Oliveira JC, Delsin LE, Pezuk JA, Valera ET, Carlotti CGJr, Rego EM, de Oliveira HF, Scrideli CA, Umezawa K, Tone LG. Inhibition of NF- kappa B by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and gamma -Radiation Cytotoxicity in Glioblastoma Cells. Chemother Res Pract. 2013;2013:593020. https://doi.org/10.1155/2013/593020

Watanabe M, Umezawa K, Higashihara M, Horie R. Combined inhibition of NF-kappaB and Bcl-2 triggers synergistic reduction of viability and induces apoptosis in melanoma cells. Oncol Res. 2013;21(4):173-80. https://doi.org/10.3727/096504014x13887748696707

Park JW, Yeh MW, Wong MG, Lobo M, Hyun WC, Duh QY, Clark OH. The heat shock protein 90-binding geldanamycin inhibits cancer cell proliferation, down-regulates oncoproteins, and inhibits epidermal growth factor-induced invasion in thyroid cancer cell lines. J Clin Endocrinol Metab. 2003;88(7):3346-53. https://doi.org/10.1210/jc.2002-020340

Wang C, Zhang R, Tan J, Meng Z, Zhang Y, Li N, Wang H, Chang J, Wang R. Effect of mesoporous silica nanoparticles coloading with 17AAG and Torin2 on anaplastic thyroid carcinoma by targeting VEGFR2. Oncol Rep. 2020;43(5):1491-502. https://doi.org/10.3892/or.2020.7537

Butler TAJ, Paul JW, Chan E-C, Smith R, Tolosa JM. Misleading Westerns: Common Quantification Mistakes in Western Blot Densitometry and Proposed Corrective Measures. BioMed Research International. 2019;2019:5214821. https://doi.org/10.1155/2019/5214821

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Published

2021-03-19

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1.
Todorović L, Stamenković G, Vučetić Tadić B, Umezawa K, Božović A, Yamashita S, Stanojević B. Synergistic effect of 17-allylamino-17-demethoxygeldanamycin with dehydroxymethylepoxyquinomicin on the human anaplastic thyroid carcinoma cell line KTC2. Arch Biol Sci [Internet]. 2021Mar.19 [cited 2024Dec.22];73(1):31-8. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/6068

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Vol. 73 No. 1 (2021)

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