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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Synergistic Combination of Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid and Natural Flavonoid Curcumin Exhibits Anticancer and Antibacterial Activity

Author(s): Ergül M. Altundağ*, Kübra Toprak, Gizem Şanlıtürk, Mümtaz Güran, Cahit Özbilenler, Namık R. Kerküklü, Ayşe M. Yılmaz and Ahmet S. Yalçın

Volume 21, Issue 10, 2021

Published on: 06 October, 2020

Page: [1301 - 1308] Pages: 8

DOI: 10.2174/1871520620666201006141317

Price: $65

Abstract

Background and Objective: Curcumin is an effective anti-cancer agent used in thyroid cancer treatments. However, its use in clinical applications is limited due to low solubility and bioavailability. In this study, a novel combination strategy was applied by combining curcumin with Suberoylanilide Hydroxamic Acid (SAHA) to increase both bioavailability of curcumin and the efficiency of SAHA, which have limited efficiency when used alone.

Methods: MTT assay was used to determine the cell viability of B-CPAP cells upon treatment with SAHA, curcumin and their combinations. Synergistic interactions between two agents were analyzed by Calcusyn software. Apoptosis and cell cycle assays were measured by flow cytometry. Expressions of apoptotic and cell cyclerelated proteins (PARP, P21/CDKN1A/WAF1, P27/KIP1) were examined by western blot analysis. Broth microdilution assay was performed to determine Minimum Inhibitory Concentration (MIC) values against S. aureus.

Results: Based on MTT assay, IC50 values for SAHA and curcumin were determined as 0.91μM and 20.97μM, respectively. The combination index CI value was determined as 0.891 in B-CPAP cells, which demonstrate synergistic activity. The apoptotic effect was achieved by combination treatment (51.85%) on B-CPAP cells using half of the dose required for SAHA and curcumin alone. Combination treatment showed a significant increase in the percentage of B-CPAP cells in the S-phase due to cell arrest. Cleaved-PARP, P21/CDKN1A/ WAF1 and P27/KIP1 protein expressions were upregulated. Curcumin was found to have better anti-microbial activity than SAHA as having a lower MIC value, and checkerboard synergy analysis revealed that the two compounds co-operate synergistically for the in vitro killing of S. aureus.

Conclusion: In the present study, synergistic combinations of SAHA and curcumin were shown to have both anti-cancer and antibacterial activities that would provide a novel thyroid cancer treatment strategy.

Keywords: B-CPAP cells, SAHA, curcumin, apoptosis, anti-microbial activity, histone deacetylase inhibitor.

Graphical Abstract
[1]
Fagin, J.A.; Wells, S.A., Jr Biologic and clinical perspectives on thyroid cancer. N. Engl. J. Med., 2016, 375(11), 1054-1067.
[http://dx.doi.org/10.1056/NEJMra1501993] [PMID: 27626519]
[2]
Lippi, F.; Picone, A. Differentiated thyroid cancer: New strategy of treatment. EC Endocrinol. Metab. Res., 2018, 3, 222-224.
[3]
Xu, J.; Hershman, J.M. Histone deacetylase inhibitor depsipeptide represses nicotinamide N-methyltransferase and hepatocyte nuclear factor-1β gene expression in human papillary thyroid cancer cells. Thyroid, 2006, 16(2), 151-160.
[http://dx.doi.org/10.1089/thy.2006.16.151] [PMID: 16676400]
[4]
Zarnegar, R.; Brunaud, L.; Kanauchi, H.; Wong, M.; Fung, M.; Ginzinger, D.; Duh, Q.Y.; Clark, O.H.; Kinder, B.K.; Zeiger, M.A.; Zielke, A. Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using Trichostatin A, a histone deacetylase inhibitor. Surgery, 2002, 132(6), 984-990.
[http://dx.doi.org/10.1067/msy.2002.128690] [PMID: 12490845]
[5]
Fortunati, N.; Catalano, M.G.; Arena, K.; Brignardello, E.; Piovesan, A.; Boccuzzi, G. Valproic acid induces the expression of the Na+/I- symporter and iodine uptake in poorly differentiated thyroid cancer cells. J. Clin. Endocrinol. Metab., 2004, 89(2), 1006-1009.
[http://dx.doi.org/10.1210/jc.2003-031407] [PMID: 14764827]
[6]
Puppin, C.; D’Aurizio, F.; D’Elia, A.V.; Cesaratto, L.; Tell, G.; Russo, D.; Filetti, S.; Ferretti, E.; Tosi, E.; Mattei, T.; Pianta, A.; Pellizzari, L.; Damante, G. Effects of histone acetylation on NIS promoter and expression of thyroid-specific transcription factors. Endocrinology, 2005, 146(9), 3967-3974.
[http://dx.doi.org/10.1210/en.2005-0128] [PMID: 15919754]
[7]
Hou, P.; Bojdani, E.; Xing, M. Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways. J. Clin. Endocrinol. Metab., 2010, 95(2), 820-828.
[http://dx.doi.org/10.1210/jc.2009-1888] [PMID: 20008023]
[8]
Catalano, M.G.; Fortunati, N.; Pugliese, M.; Costantino, L.; Poli, R.; Bosco, O.; Boccuzzi, G. Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells. J. Clin. Endocrinol. Metab., 2005, 90(3), 1383-1389.
[http://dx.doi.org/10.1210/jc.2004-1355] [PMID: 15585556]
[9]
Mutlu Altundağ, E.; Kasacı, T.; Yılmaz, A.M.; Karademir, B.; Koçtürk, S.; Taga, Y.; Yalçın, A.S. Quercetin-induced cell death in human papillary thyroid cancer (B-CPAP) cells. J. Thyroid Res., 2016, 2016, 9843675.
[http://dx.doi.org/10.1155/2016/9843675] [PMID: 27057371]
[10]
Kocaadam, B.; Şanlier, N. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit. Rev. Food Sci. Nutr., 2017, 57(13), 2889-2895.
[http://dx.doi.org/10.1080/10408398.2015.1077195] [PMID: 26528921]
[11]
Kunnumakkara, A.B.; Bordoloi, D.; Harsha, C.; Banik, K.; Gupta, S.C.; Aggarwal, B.B. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways. Clin. Sci. (Lond.), 2017, 131(15), 1781-1799.
[http://dx.doi.org/10.1042/CS20160935] [PMID: 28679846]
[12]
Mutlu Altundağ, E.; Yılmaz, A.M.; Koçtürk, S.; Taga, Y.; Yalçın, A.S. Synergistic induction of apoptosis by quercetin and curcumin in chronic myeloid leukemia (K562) cells. Nutr. Cancer, 2018, 70(1), 97-108.
[http://dx.doi.org/10.1080/01635581.2018.1380208] [PMID: 29161179]
[13]
Mutlu Altundağ, E.; Yılmaz, A.M.; Serdar, B.S.; Jannuzzi, A.T.; Koçtürk, S.; Yalçın, A.S. Synergistic induction of apoptosis by quercetin and curcumin in chronic myeloid leukemia (K562) cells: II. Signal transduction pathways involved. Nutr. Cancer, 2020, 1-10.
[14]
Zhang, W.; Bai, W.; Zhang, W. MiR-21 suppresses the anticancer activities of curcumin by targeting PTEN gene in human non-small cell lung cancer A549 cells. Clin. Transl. Oncol., 2014, 16(8), 708-713.
[http://dx.doi.org/10.1007/s12094-013-1135-9] [PMID: 24293118]
[15]
Mulik, R.S.; Mönkkönen, J.; Juvonen, R.O.; Mahadik, K.R.; Paradkar, A.R. Transferrin mediated solid lipid nanoparticles containing curcumin: Enhanced in vitro anticancer activity by induction of apoptosis. Int. J. Pharm., 2010, 398(1-2), 190-203.
[http://dx.doi.org/10.1016/j.ijpharm.2010.07.021] [PMID: 20655375]
[16]
Yallapu, M.M.; Khan, S.; Maher, D.M.; Ebeling, M.C.; Sundram, V.; Chauhan, N.; Ganju, A.; Balakrishna, S.; Gupta, B.K.; Zafar, N.; Jaggi, M.; Chauhan, S.C. Anti-cancer activity of curcumin loaded nanoparticles in prostate cancer. Biomaterials, 2014, 35(30), 8635-8648.
[http://dx.doi.org/10.1016/j.biomaterials.2014.06.040] [PMID: 25028336]
[17]
Mulik, R.S.; Mönkkönen, J.; Juvonen, R.O.; Mahadik, K.R.; Paradkar, A.R. ApoE3 mediated polymeric nanoparticles containing curcumin: Apoptosis induced in vitro anticancer activity against neuroblastoma cells. Int. J. Pharm., 2012, 437(1-2), 29-41.
[http://dx.doi.org/10.1016/j.ijpharm.2012.07.062] [PMID: 22890189]
[18]
Tomeh, M.A.; Hadianamrei, R.; Zhao, X. A review of curcumin and its derivatives as anticancer agents. Int. J. Mol. Sci., 2019, 20(5), E1033.
[http://dx.doi.org/10.3390/ijms20051033] [PMID: 30818786]
[19]
Moghadamtousi, S.Z.; Kadir, H.A.; Hassandarvish, P.; Tajik, H.; Abubakar, S.; Zandi, K. A review on antibacterial, antiviral, and antifungal activity of curcumin. BioMed Res. Int., 2014, 2014, 186864.
[http://dx.doi.org/10.1155/2014/186864] [PMID: 24877064]
[20]
Corpas-López, V.; Díaz-Gavilán, M.; Franco-Montalbán, F.; Merino-Espinosa, G.; López-Viota, M.; López-Viota, J.; Belmonte-Reche, E.; Pérez-Del Palacio, J.; de Pedro, N.; Gómez-Vidal, J.A.; Morillas-Márquez, F.; Martín-Sánchez, J. A nanodelivered Vorinostat derivative is a promising oral compound for the treatment of visceral leishmaniasis. Pharmacol. Res., 2019, 139, 375-383.
[http://dx.doi.org/10.1016/j.phrs.2018.11.039] [PMID: 30503838]
[21]
Li, Y.; Liu, M.; Rizk, M.A.; Moumouni, P.F.A.; Lee, S-H.; Galon, E.M.; Guo, H.; Gao, Y.; Li, J.; Beshbishy, A.M.; Nugraha, A.B.; Ji, S.; Tumwebaze, M.A.; Benedicto, B.; Yokoyama, N.; Igarashi, I.; Xuan, X. Drug screening of food and drug administration-approved compounds against Babesia bovis in vitro. Exp. Parasitol., 2020, 210, 107831.
[http://dx.doi.org/10.1016/j.exppara.2020.107831] [PMID: 31926147]
[22]
Chou, T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res., 2010, 70(2), 440-446.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1947] [PMID: 20068163]
[23]
Laemmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 1970, 227(5259), 680-685.
[http://dx.doi.org/10.1038/227680a0] [PMID: 5432063]
[24]
Schwalbe, R.; Steele-Moore, L.; Goodwin, A.C. Antimicrobial Susceptibility Testing Protocols; CRC Press: USA, 2007.
[http://dx.doi.org/10.1201/9781420014495]
[25]
Garvey, M.I.; Rahman, M.M.; Gibbons, S.; Piddock, L.J.V. Medicinal plant extracts with efflux inhibitory activity against Gram-negative bacteria. Int. J. Antimicrob. Agents, 2011, 37(2), 145-151.
[http://dx.doi.org/10.1016/j.ijantimicag.2010.10.027] [PMID: 21194895]
[26]
Shi, X.Y.; Ding, W.; Li, T.Q.; Zhang, Y.X.; Zhao, S.C. Histone Deacetylase (HDAC) inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), induces apoptosis in prostate cancer cell lines via the Akt/FOXO3a signaling pathway. Med. Sci. Monit., 2017, 23, 5793-5802.
[http://dx.doi.org/10.12659/MSM.904597] [PMID: 29211704]
[27]
Steed, K.L.; Jordan, H.R.; Tollefsbol, T.O. SAHA and EGCG promote apoptosis in triple-negative breast cancer cells, possibly through the modulation of cIAP2. Anticancer Res., 2020, 40(1), 9-26.
[http://dx.doi.org/10.21873/anticanres.13922] [PMID: 31892549]
[28]
Kyaw, M.T.H.; Yamaguchi, Y.; Choijookhuu, N.; Yano, K.; Takagi, H.; Takahashi, N.; Synn Oo, P.; Sato, K.; Hishikawa, Y. The HDAC inhibitor, SAHA, combined with cisplatin synergistically induces apoptosis in alpha-fetoprotein-producing hepatoid adenocarcinoma cells. Acta Histochem. Cytochem., 2019, 52(1), 1-8.
[http://dx.doi.org/10.1267/ahc.18044] [PMID: 30923410]
[29]
Altundag, E.M.; Yilmaz, A.M.; Corek, C.; Yalcin, A.S.; Yavuz, T.; Kocturk, S. Synergistic effects of methotrexate and suberoylanilide hydroxamic acid in triggering apoptosis of chronic myeloid leukemia cells. Int. J. Hematol. Oncol., 2015, 29(4), 1-11.
[30]
Zhao, Y.; Yu, D.; Wu, H.; Liu, H.; Zhou, H.; Gu, R.; Zhang, R.; Zhang, S.; Wu, G. Anticancer activity of SAHA, a potent histone deacetylase inhibitor, in NCI-H460 human large-cell lung carcinoma cells in vitro and in vivo. Int. J. Oncol., 2014, 44(2), 451-458.
[http://dx.doi.org/10.3892/ijo.2013.2193] [PMID: 24297449]
[31]
Meng, J.; Li, Y.; Camarillo, C.; Yao, Y.; Zhang, Y.; Xu, C.; Jiang, L. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity. PLoS One, 2014, 9(1), e85570.
[http://dx.doi.org/10.1371/journal.pone.0085570] [PMID: 24409332]
[32]
Khan, A.Q.; Ahmed, E.I.; Elareer, N.; Fathima, H.; Prabhu, K.S.; Siveen, K.S.; Kulinski, M.; Azizi, F.; Dermime, S.; Ahmad, A.; Steinhoff, M.; Uddin, S. Curcumin-mediated apoptotic cell death in papillary thyroid cancer and cancer stem-like cells through targeting of the JAK/STAT3 signaling pathway. Int. J. Mol. Sci., 2020, 21(2), 438.
[http://dx.doi.org/10.3390/ijms21020438] [PMID: 31936675]
[33]
Marks, P.A. The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opin. Investig. Drugs, 2010, 19(9), 1049-1066.
[http://dx.doi.org/10.1517/13543784.2010.510514] [PMID: 20687783]
[34]
Mun, S.H.; Joung, D.K.; Kim, Y.S.; Kang, O.H.; Kim, S.B.; Seo, Y.S.; Kim, Y.C.; Lee, D.S.; Shin, D.W.; Kweon, K.T.; Kwon, D.Y. Synergistic antibacterial effect of curcumin against methicillin-resistant Staphylococcus aureus. Phytomedicine, 2013, 20(8-9), 714-718.
[http://dx.doi.org/10.1016/j.phymed.2013.02.006] [PMID: 23537748]
[35]
Güran, M.; Şanlıtürk, G.; Kerküklü, N.R.; Altundağ, E.M.; Süha Yalçın, A. Combined effects of quercetin and curcumin on anti-inflammatory and antimicrobial parameters in vitro. Eur. J. Pharmacol., 2019, 859(June), 172486.
[http://dx.doi.org/10.1016/j.ejphar.2019.172486] [PMID: 31251919]
[36]
Allavena, G.; Debellis, D.; Marotta, R.; Joshi, C.S.; Mysorekar, I.U.; Grimaldi, B. A broad-spectrum antibiotic, DCAP, reduces uropathogenic Escherichia coli infection and enhances vorinostat anticancer activity by modulating autophagy. Cell Death Dis., 2018, 9(7), 780.
[http://dx.doi.org/10.1038/s41419-018-0786-4] [PMID: 30006504]
[37]
Adpressa, D.A.; Stalheim, K.J.; Proteau, P.J.; Loesgen, S. Unexpected biotransformation of the HDAC inhibitor vorinostat yields aniline-containing fungal metabolites. ACS Chem. Biol., 2017, 12(7), 1842-1847.
[http://dx.doi.org/10.1021/acschembio.7b00268] [PMID: 28530797]
[38]
Masadeh, M.M.; Alzoubi, K.H.; Al-Azzam, S.I.; Al-Buhairan, A.M. Possible involvement of ROS generation in vorinostat pretreatment induced enhancement of the antibacterial activity of ciprofloxacin. Clin. Pharmacol., 2017, 9, 119-124.
[http://dx.doi.org/10.2147/CPAA.S148448] [PMID: 29081676]

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