Evodiamine in combination with histone deacetylase inhibitors has synergistic cytotoxicity in thyroid carcinoma cells
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The impact of evodiamine in combination with histone deacetylase (HDAC) inhibitors on survival of thyroid carcinoma cells was identified.
TPC-1 and SW1736 human thyroid carcinoma cells were used.
After treatment with evodiamine and PXD101, cell viability, the percentage of viable cells and Bcl2 protein levels decreased, whereas cytotoxic activity, the percentage of apoptotic cells, the protein levels of γH2AX, acetyl. histone H3 and cleaved PARP, and reactive oxygen species (ROS) production increased. In cells treated with both evodiamine and PXD101, compared with PXD101 alone, decrement of cell viability, the percentage of viable cells, and Bcl2 protein levels as well as increment of cytotoxic activity, the percentage of apoptotic cells, the protein levels of γH2AX and cleaved PARP, and ROS production were significant, causing decrement of Bcl2/Bax ratio. Furthermore, all of the combination index values were <1.0, suggesting synergistic cytotoxicity of two agents. Wortmannin decreased cell viability and the percentage of viable cells, whereas it increased cytotoxic activity and the percentage of apoptotic cells without alteration in ROS production. The changes in cells treated with both evodiamine and suberoylanilide hydroxamic acid or trichostatin A were similar to those in cells treated with both evodiamine and PXD101.
Our results demonstrate that evodiamine synergizes with HDAC inhibitors in inducing cytotoxic activities by involving survival-related proteins and ROS in thyroid carcinoma cells. Moreover, repression of PI3K/Akt signaling synergistically reinforces cytotoxicity of evodiamine combined with HDAC inhibitors in thyroid carcinoma cells.
KeywordsThyroid carcinoma Evodiamine HDAC inhibitor Synergism Akt
anaplastic thyroid carcinoma
the concentrations of each drug required for 50% inhibition
follicular thyroid cancer
poly (ADP-ribose) polymerase
papillary thyroid cancer
reactive oxygen species
suberoylanilide hydroxamic acid
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2018R1D1A1B07044901) to S.J.L.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.B.R. Haugen, E.K. Alexander, K.C. Bible, G.M. Doherty, S.J. Mandel, Y.E. Nikiforov, F. Pacini, G.W. Randolph, A.M. Sawka, M. Schlumberger, K.G. Schuff, S.I. Sherman, J.A. Sosa, D.L. Steward, R.M. Tuttle, L. Wartofsky, 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26, 1–133 (2016)CrossRefGoogle Scholar
- 3.R.C. Smallridge, K.B. Ain, S.L. Asa, K.C. Bible, J.D. Brierley, K.D. Burman, E. Kebebew, N.Y. Lee, Y.E. Nikiforov, M.S. Rosenthal, M.H. Shah, A.R. Shaha, R.M. Tuttle, American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 22, 1104–1139 (2012)CrossRefGoogle Scholar
- 6.Y. Takada, Y. Kobayashi, B.B. Aggarwal, Evodiamine abolishes constitutive and inducible NF-kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF-kappaB-regulated antiapoptotic and metastatic gene expression, up-regulating apoptosis, and inhibiting invasion. J. Biol. Chem. 280, 17203–17212 (2005)CrossRefGoogle Scholar
- 16.C.H. Liao, S.L. Pan, J.H. Guh, Y.L. Chang, H.C. Pai, C.H. Lin, C.M. Teng, Antitumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus, in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo. Carcinogenesis 26, 968–975 (2005)CrossRefGoogle Scholar
- 22.S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Novel heat shock protein 90 inhibitor NVP-AUY922 synergizes with the histone deacetylase inhibitor PXD101 in induction of death of anaplastic thyroid carcinoma cells. J. Clin. Endocrinol. Metab. 100, E253–E261 (2015)CrossRefGoogle Scholar
- 25.I. Clinckspoor, L. Verlinden, L. Overbergh, C. Korch, R. Bouillon, C. Mathieu, A. Verstuyf, B. Decallonne, 1,25-dihydroxyvitamin D3 and a superagonistic analog in combination with paclitaxel or suberoylanilide hydroxamic acid have potent antiproliferative effects on anaplastic thyroid cancer. J. Steroid Biochem. Mol. Biol. 124, 1–9 (2011)CrossRefGoogle Scholar
- 28.Y.L. Li, N.Y. Zhang, X. Hu, J.L. Chen, M.J. Rao, L.W. Wu, Q.Y. Li, B. Zhang, W. Yan, C. Zhang, Evodiamine induces apoptosis and promotes hepatocellular carcinoma cell death induced by vorinostat via downregulating HIF-1α under hypoxia. Biochem. Biophys. Res. Commun. 498, 481–486 (2018)CrossRefGoogle Scholar
- 30.S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Hsp70 inhibition potentiates radicicol-induced cell death in anaplastic thyroid carcinoma cells. Anticancer Res. 34, 4829–4837 (2014)Google Scholar
- 34.S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Gemigliptin, a novel dipeptidyl peptidase-IV inhibitor, exerts a synergistic cytotoxicity with the histone deacetylase inhibitor PXD101 in thyroid carcinoma cells. J. Endocrinol. Invest. 41, 677–689 (2018)CrossRefGoogle Scholar
- 36.S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Akt inhibition enhances the cytotoxic effect of apigenin in combination with PLX4032 in anaplastic thyroid carcinoma cells harboring BRAFV600E. J. Endocrinol. Invest. 36, 1099–1104 (2013)Google Scholar
- 38.S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Suppression of AKT potentiates synergistic cytotoxicity of apigenin with TRAIL in anaplastic thyroid carcinoma cells. Anticancer Res. 35, 6529–6537 (2015)Google Scholar
- 41.R.E. Schweppe, J.P. Klopper, C. Korch, U. Pugazhenthi, M. Benezra, J.A. Knauf, J.A. Fagin, L.A. Marlow, J.A. Copland, R.C. Smallridge, B.R. Haugen, Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J. Clin. Endocrinol. Metab. 93, 4331–4341 (2008)CrossRefGoogle Scholar
- 42.Z. Lv, D. Zhao, R. Liu, J. Guo, Y. Lin, M. Zhang, Evodiamine inhibits proliferation of human papillary thyroid cancer cell line K1 by regulating of PI3K/Akt signaling pathway. Int. J. Clin. Exp. Med. 9, 15216–15225 (2016)Google Scholar