Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Proteomics Analysis Revealed Smad3 as a Potential Target of the Synergistic Antitumor Activity of Disulfiram and Cisplatin in Ovarian Cancer

Author(s): Ruiping Du, Feilong Sun, Kai Li, Jian Qi, Wen Zhong, Wei Wang, Qiuyan Sun, Qingmei Deng, Hongzhi Wang, Jinfu Nie, Chen Ding* and Bo Hong*

Volume 23, Issue 15, 2023

Published on: 05 June, 2023

Page: [1754 - 1764] Pages: 11

DOI: 10.2174/1871520623666230516161200

Price: $65

Abstract

Introduction: Among gynecological cancers, ovarian cancer has a high mortality rate. Cisplatin-based chemotherapy is commonly used for the treatment of ovarian cancer. However, the clinical efficacy of cisplatin in ovarian cancer is limited due to the development of chemo-resistance during treatment.

Objective: In the study, we aimed to investigate the synergistic anti-cancer activity and targets of the FDA-approved drug disulfiram combined with cisplatin in ovarian cancer.

Methods: The cell viability was determined by Celltier-Glo luminescent assay. The synergistic anti-cancer activity was assessed by combination index. Cell cycle and apoptosis were detected by flow cytometry. The in vivo anti-tumor activity and side effects were evaluated using a xenografted mice model. The synergistic anti-cancer targets were identified by a mass spectrometry-based proteomics analysis.

Results: In this study, we first found that disulfiram synergistically enhanced the anti-tumor activity of cisplatin in chemo-resistant ovarian cancer cells, which was accompanied by the enhanced induction of cellular apoptosis. Secondly, the in vivo study demonstrated that the combination treatment of disulfiram and cisplatin dramatically inhibited tumor growth and had no apparent side effects in ovarian cancer xenografted mice. Finally, proteomics analysis identified SMAD3 as a potential target of disulfiram-cisplatin combined treatment, and the down-regulation of SMAD3 could increase cisplatin-induced cell death in ovarian cancer.

Conclusion: Combination treatment of disulfiram and cisplatin synergistically inhibited the growth of ovarian cancer through down-regulating SMAD3. As a repurposed drug, disulfiram could be quickly transformed into a clinic to overcome cisplatin resistance for the treatment of ovarian cancer.

« Previous Next »
Graphical Abstract

[1]
Zhang, S.; Sun, K.; Zheng, R.; Zeng, H.; Wang, S.; Chen, R.; Wei, W.; He, J. Cancer incidence and mortality in China, 2015. J. Natl. Cancer Inst., 2021, 1(1), 2-11.
[http://dx.doi.org/10.1016/j.jncc.2020.12.001]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin., 2017, 67(1), 7-30.
[http://dx.doi.org/10.3322/caac.21387] [PMID: 28055103]
[3]
Matulonis, U.A.; Sood, A.K.; Fallowfield, L.; Howitt, B.E.; Sehouli, J.; Karlan, B.Y. Ovarian cancer. Nat. Rev. Dis. Primers, 2016, 2(1), 16061.
[http://dx.doi.org/10.1038/nrdp.2016.61] [PMID: 27558151]
[4]
Mirahmadi, Y.; Nabavi, R.; Taheri, F.; Samadian, M.M.; Ghale-Noie, Z.N.; Farjami, M.; Samadi-khouzani, A.; Yousefi, M.; Azhdari, S.; Salmaninejad, A.; Sahebkar, A. MicroRNAs as biomarkers for early diagnosis, prognosis, and therapeutic targeting of ovarian cancer. J. Oncol., 2021, 2021, 1-25.
[http://dx.doi.org/10.1155/2021/3408937] [PMID: 34721577]
[5]
Jiao, Y.; Hannafon, B.N.; Ding, W.Q. Disulfiram’s anticancer activity: Evidence and mechanisms. Anticancer. Agents Med. Chem., 2016, 16(11), 1378-1384.
[http://dx.doi.org/10.2174/1871520615666160504095040] [PMID: 27141876]
[6]
Skrott, Z.; Majera, D.; Gursky, J.; Buchtova, T.; Hajduch, M.; Mistrik, M.; Bartek, J. Disulfiram’s anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase. Oncogene, 2019, 38(40), 6711-6722.
[http://dx.doi.org/10.1038/s41388-019-0915-2] [PMID: 31391554]
[7]
Yip, N.C.; Fombon, I.S.; Liu, P.; Brown, S.; Kannappan, V.; Armesilla, A.L.; Xu, B.; Cassidy, J.; Darling, J.L.; Wang, W. Disulfiram modulated ROS–MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br. J. Cancer, 2011, 104(10), 1564-1574.
[http://dx.doi.org/10.1038/bjc.2011.126] [PMID: 21487404]
[8]
Viola-Rhenals, M.; Patel, K.R.; Jaimes-Santamaria, L.; Wu, G.; Liu, J.; Dou, Q.P. Recent advances in antabuse (Disulfiram): The importance of its metal-binding ability to its anticancer activity. Curr. Med. Chem., 2018, 25(4), 506-524.
[http://dx.doi.org/10.2174/0929867324666171023161121] [PMID: 29065820]
[9]
Terashima, Y.; Toda, E.; Itakura, M.; Otsuji, M.; Yoshinaga, S.; Okumura, K.; Shand, F.H.W.; Komohara, Y.; Takeda, M.; Kokubo, K.; Chen, M.C.; Yokoi, S.; Rokutan, H.; Kofuku, Y.; Ohnishi, K.; Ohira, M.; Iizasa, T.; Nakano, H.; Okabe, T.; Kojima, H.; Shimizu, A.; Kanegasaki, S.; Zhang, M.R.; Shimada, I.; Nagase, H.; Terasawa, H.; Matsushima, K. Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties. Nat. Commun., 2020, 11(1), 609.
[http://dx.doi.org/10.1038/s41467-020-14338-5] [PMID: 32001710]
[10]
Lun, X.; Wells, J.C.; Grinshtein, N.; King, J.C.; Hao, X.; Dang, N.H.; Wang, X.; Aman, A.; Uehling, D.; Datti, A.; Wrana, J.L.; Easaw, J.C.; Luchman, A.; Weiss, S.; Cairncross, J.G.; Kaplan, D.R.; Robbins, S.M.; Senger, D.L. Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma. Clin. Cancer Res., 2016, 22(15), 3860-3875.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1798] [PMID: 27006494]
[11]
Allensworth, J.L.; Evans, M.K.; Bertucci, F.; Aldrich, A.J.; Festa, R.A.; Finetti, P.; Ueno, N.T.; Safi, R.; McDonnell, D.P.; Thiele, D.J.; Van Laere, S.; Devi, G.R. Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol. Oncol., 2015, 9(6), 1155-1168.
[http://dx.doi.org/10.1016/j.molonc.2015.02.007] [PMID: 25769405]
[12]
Kita, Y.; Hamada, A.; Saito, R.; Teramoto, Y.; Tanaka, R.; Takano, K.; Nakayama, K.; Murakami, K.; Matsumoto, K.; Akamatsu, S.; Yamasaki, T.; Inoue, T.; Tabata, Y.; Okuno, Y.; Ogawa, O.; Kobayashi, T. Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: A summary of preclinical studies. Br. J. Cancer, 2019, 121(12), 1027-1038.
[http://dx.doi.org/10.1038/s41416-019-0609-0] [PMID: 31673101]
[13]
Song, W.; Tang, Z.; Shen, N.; Yu, H.; Jia, Y.; Zhang, D.; Jiang, J.; He, C.; Tian, H.; Chen, X. Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance. J. Control. Release, 2016, 231, 94-102.
[http://dx.doi.org/10.1016/j.jconrel.2016.02.039] [PMID: 26928530]
[14]
Moreb, J.S.; Ucar, D.; Han, S.; Amory, J.K.; Goldstein, A.S.; Ostmark, B.; Chang, L.J. The enzymatic activity of human aldehyde dehydrogenases 1A2 and 2 (ALDH1A2 and ALDH2) is detected by Aldefluor, inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance. Chem. Biol. Interact., 2012, 195(1), 52-60.
[http://dx.doi.org/10.1016/j.cbi.2011.10.007] [PMID: 22079344]
[15]
Hu, L.; Chen, M.; Chen, X.; Zhao, C.; Fang, Z.; Wang, H.; Dai, H. Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate. Cell Death Dis., 2020, 11(4), 281.
[http://dx.doi.org/10.1038/s41419-020-2476-2] [PMID: 32332857]
[16]
Liu, X.; Wang, W.; Yin, Y.; Li, M.; Li, H.; Xiang, H.; Xu, A.; Mei, X.; Hong, B.; Lin, W. A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer. Invest. New Drugs, 2019, 37(6), 1166-1176.
[http://dx.doi.org/10.1007/s10637-019-00750-2] [PMID: 30825105]
[17]
Yin, Y.; Shi, W.; Deng, K.; Liu, X.; Li, H.; Lv, X.; Lui, V.W.Y.; Ding, C.; Hong, B.; Lin, W. Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer. Acta Pharmacol. Sin., 2021, 42(8), 1298-1310.
[http://dx.doi.org/10.1038/s41401-020-00544-w] [PMID: 33139838]
[18]
Jangra, A.; Choi, S.A.; Yang, J.; Koh, E.J.; Phi, J.H.; Lee, J.Y.; Wang, K.C.; Kim, S.K. Disulfiram potentiates the anticancer effect of cisplatin in atypical teratoid/rhabdoid tumors (AT/RT). Cancer Lett., 2020, 486, 38-45.
[http://dx.doi.org/10.1016/j.canlet.2020.05.006] [PMID: 32428661]
[19]
Wang, H.; Hong, B.; Li, X.; Deng, K.; Li, H.; Yan Lui, V.W.; Lin, W. JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN -amplified small cell lung cancer. Oncotarget, 2017, 8(49), 86312-86324.
[http://dx.doi.org/10.18632/oncotarget.21146] [PMID: 29156797]
[20]
Ashton, J.C. Drug combination studies and their synergy quantification using the Chou-Talalay method--letter. Cancer Res., 2015, 75(11), 2400.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-3763] [PMID: 25977339]
[21]
Hao, Y.; Baker, D.; ten Dijke, P. TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis. Int. J. Mol. Sci., 2019, 20(11), 2767.
[http://dx.doi.org/10.3390/ijms20112767] [PMID: 31195692]
[22]
Sabbadini, F.; Bertolini, M.; De Matteis, S.; Mangiameli, D.; Contarelli, S.; Pietrobono, S.; Melisi, D. The multifaceted role of tgf-β in gastrointestinal tumors. Cancers , 2021, 13(16), 3960.
[http://dx.doi.org/10.3390/cancers13163960] [PMID: 34439114]
[23]
Xie, Y.; Zhu, S.; Zang, J.; Wu, G.; Wen, Y.; Liang, Y.; Long, Y.; Guo, W.; Zang, C.; Hu, X.; Fan, G.; Xiang, S.; Zhang, J. ADNP prompts the cisplatin-resistance of bladder cancer via TGF-β-mediated epithelial-mesenchymal transition (EMT) pathway. J. Cancer, 2021, 12(17), 5114-5124.
[http://dx.doi.org/10.7150/jca.58049] [PMID: 34335928]
[24]
Yin, J.; Wang, L.; Wang, Y.; Shen, H.; Wang, X.; Wu, L. Curcumin reverses oxaliplatin resistance in human colorectal cancer via regulation of TGF-β/Smad2/3 signaling pathway. OncoTargets Ther., 2019, 12, 3893-3903.
[http://dx.doi.org/10.2147/OTT.S199601] [PMID: 31190888]
[25]
Ji, H.; Li, K.; Xu, W.; Li, R.; Xie, S.; Zhu, X. Prediction of the mechanisms by which quercetin enhances cisplatin action in cervical cancer: A network pharmacology study and experimental validation. Front. Oncol., 2022, 11, 780387.
[http://dx.doi.org/10.3389/fonc.2021.780387] [PMID: 35070983]
[26]
Liang, F.; Ren, C.; Wang, J.; Wang, S.; Yang, L.; Han, X.; Chen, Y.; Tong, G.; Yang, G. The crosstalk between STAT3 and p53/RAS signaling controls cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy. Oncogenesis, 2019, 8(10), 59.
[http://dx.doi.org/10.1038/s41389-019-0165-8] [PMID: 31597912]
[27]
Chatterjee, N.; Whitman, M.A.; Harris, C.A.; Min, S.M.; Jonas, O.; Lien, E.C.; Luengo, A.; Vander Heiden, M.G.; Hong, J.; Zhou, P.; Hemann, M.T.; Walker, G.C. REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks. Proc. Natl. Acad. Sci., 2020, 117(46), 28918-28921.
[http://dx.doi.org/10.1073/pnas.2016064117] [PMID: 33168727]
[28]
Mohammad, I.S.; Teng, C.; Chaurasiya, B.; Yin, L.; Wu, C.; He, W. Drug-delivering-drug approach-based codelivery of paclitaxel and disulfiram for treating multidrug-resistant cancer. Int. J. Pharm., 2019, 557, 304-313.
[http://dx.doi.org/10.1016/j.ijpharm.2018.12.067] [PMID: 30599232]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy