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

Monensin Inhibits Anaplastic Thyroid Cancer via Disrupting Mitochondrial Respiration and AMPK/mTOR Signaling

Author(s): Yanli Li, Qianshu Sun, Sisi Chen, Xiongjie Yu and Hongxia Jing*

Volume 22, Issue 14, 2022

Published on: 06 April, 2022

Page: [2539 - 2547] Pages: 9

DOI: 10.2174/1871520622666220215123620

Price: $65

Abstract

Objective: The clinical management of anaplastic thyroid cancer (ATC) remains challenging, and novel treatment methods are needed. Monensin is a carboxyl polyether ionophore that potently inhibits the growth of various cancer types. Our current work investigates whether monensin has selective anti-ATC activity and systematically explores its underlying mechanisms.

Methods: Proliferation and apoptosis assays were performed using a panel of thyroid cancer cell lines. Mitochondrial biogenesis profiles, ATP levels, oxidative stress, AMPK, and mTOR were examined in these cells after monensin treatment.

Results: Monensin is effective in inhibiting proliferation and inducing apoptosis in a number of thyroid cancer cell lines. The results are consistent across cell lines of varying cellular origins and genetic mutations. Compared to other thyroid cancer cell types, ATC cell lines are the most sensitive to monensin. Of note, monensin used at our experimental concentration affects less of normal cells. Mechanistic studies reveal that monensin acts on ATC cells by disrupting mitochondrial function, inducing oxidative stress and damage, and AMPK activation-induced mTOR inhibition. We further show that mitochondrial respiration is a critical target for monensin in ATC cells.

Conclusions: Our pre-clinical findings demonstrate the selective anti-ATC activities of monensin. This is supported by increasing evidence that monensin can be repurposed as a potential anti-cancer drug.

Keywords: Monensin, mitochondria, oxidative stress, thyroid cancer, AMPK, mTOR.

« Previous Next »
Graphical Abstract

[1]
Kim, J.; Gosnell, J.E.; Roman, S.A. Geographic influences in the global rise of thyroid cancer. Nat. Rev. Endocrinol., 2020, 16(1), 17-29.
[http://dx.doi.org/10.1038/s41574-019-0263-x] [PMID: 31616074]
[2]
Hu, J.; Yuan, I.J.; Mirshahidi, S.; Simental, A.; Lee, S.C.; Yuan, X. Thyroid carcinoma: Phenotypic features, underlying biology and poten-tial relevance for targeting therapy. Int. J. Mol. Sci., 2021, 22(4), 1950.
[http://dx.doi.org/10.3390/ijms22041950] [PMID: 33669363]
[3]
Prete, A.; Matrone, A.; Gambale, C.; Torregrossa, L.; Minaldi, E.; Romei, C.; Ciampi, R.; Molinaro, E.; Elisei, R. Poorly differentiated and anaplastic thyroid cancer: Insights into genomics, microenvironment and new drugs. Cancers (Basel), 2021, 13(13), 3200.
[http://dx.doi.org/10.3390/cancers13133200] [PMID: 34206867]
[4]
De Leo, S.; Trevisan, M.; Fugazzola, L. Recent advances in the management of anaplastic thyroid cancer. Thyroid Res., 2020, 13(1), 17.
[http://dx.doi.org/10.1186/s13044-020-00091-w] [PMID: 33292371]
[5]
Abe, I.; Lam, A.K. Anaplastic thyroid carcinoma: Crrent issues in genomics and therapeutics. Curr. Oncol. Rep., 2021, 23(3), 31.
[http://dx.doi.org/10.1007/s11912-021-01019-9] [PMID: 33582932]
[6]
Jin, S.; Borkhuu, O.; Bao, W.; Yang, Y.T. Signaling pathways in thyroid cancer and their therapeutic implications. J. Clin. Med. Res., 2016, 8(4), 284-296.
[http://dx.doi.org/10.14740/jocmr2480w] [PMID: 26985248]
[7]
Kudryavtseva, A.V.; Krasnov, G.S.; Dmitriev, A.A.; Alekseev, B.Y.; Kardymon, O.L.; Sadritdinova, A.F.; Fedorova, M.S.; Pokrovsky, A.V.; Melnikova, N.V.; Kaprin, A.D.; Moskalev, A.A.; Snezhkina, A.V. Mitochondrial dysfunction and oxidative stress in aging and can-cer. Oncotarget, 2016, 7(29), 44879-44905.
[http://dx.doi.org/10.18632/oncotarget.9821] [PMID: 27270647]
[8]
Lee, J.; Chang, J.Y.; Kang, Y.E.; Yi, S.; Lee, M.H.; Joung, K.H.; Kim, K.S.; Shong, M. Mitochondrial energy metabolism and thyroid can-cers. Endocrinol. Metab. (Seoul), 2015, 30(2), 117-123.
[http://dx.doi.org/10.3803/EnM.2015.30.2.117] [PMID: 26194071]
[9]
Weinberg, S.E.; Chandel, N.S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol., 2015, 11(1), 9-15.
[http://dx.doi.org/10.1038/nchembio.1712] [PMID: 25517383]
[10]
Lagadinou, E.D.; Sach, A.; Callahan, K.; Rossi, R.M.; Neering, S.J.; Minhajuddin, M.; Ashton, J.M.; Pei, S.; Grose, V.; O’Dwyer, K.M.; Liesveld, J.L.; Brookes, P.S.; Becker, M.W.; Jordan, C.T. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell, 2013, 12(3), 329-341.
[http://dx.doi.org/10.1016/j.stem.2012.12.013] [PMID: 23333149]
[11]
Järås, M.; Ebert, B.L. Power cut: inhibiting mitochondrial translation to target leukemia. Cancer Cell, 2011, 20(5), 555-556.
[http://dx.doi.org/10.1016/j.ccr.2011.10.028] [PMID: 22094249]
[12]
Wang, Y.; Xie, F.; Chen, D.; Wang, L. Inhibition of mitochondrial respiration by tigecycline selectively targets thyroid carcinoma and in-creases chemosensitivity. Clin. Exp. Pharmacol. Physiol., 2019, 46(10), 890-897.
[http://dx.doi.org/10.1111/1440-1681.13126] [PMID: 31209921]
[13]
Charvat, R.A.; Arrizabalaga, G. Oxidative stress generated during monensin treatment contributes to altered Toxoplasma gondii mitochon-drial function. Sci. Rep., 2016, 6(1), 22997.
[http://dx.doi.org/10.1038/srep22997] [PMID: 26976749]
[14]
Yao, S.; Wang, W.; Zhou, B.; Cui, X.; Yang, H.; Zhang, S. Monensin suppresses cell proliferation and invasion in ovarian cancer by en-hancing MEK1 SUMOylation. Exp. Ther. Med., 2021, 22(6), 1390.
[http://dx.doi.org/10.3892/etm.2021.10826] [PMID: 34650638]
[15]
Gu, J.; Huang, L.; Zhang, Y. Monensin inhibits proliferation, migration, and promotes apoptosis of breast cancer cells via downregulating UBA2. Drug Dev. Res., 2020, 81(6), 745-753.
[http://dx.doi.org/10.1002/ddr.21683] [PMID: 32462716]
[16]
Park, W.H.; Lee, M.S.; Park, K.; Kim, E.S.; Kim, B.K.; Lee, Y.Y. Monensin-mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis. Int. J. Cancer, 2002, 101(3), 235-242.
[http://dx.doi.org/10.1002/ijc.10592] [PMID: 12209973]
[17]
Park, W.H.; Seol, J.G.; Kim, E.S.; Kang, W.K.; Im, Y.H.; Jung, C.W.; Kim, B.K.; Lee, Y.Y. Monensin-mediated growth inhibition in human lymphoma cells through cell cycle arrest and apoptosis. Br. J. Haematol., 2002, 119(2), 400-407.
[http://dx.doi.org/10.1046/j.1365-2141.2002.03834.x] [PMID: 12406077]
[18]
Hashiguchi, K.; Zhang-Akiyama, Q.M. Establishment of human cell lines lacking mitochondrial DNA. Methods Mol. Biol., 2009, 554, 383-391.
[http://dx.doi.org/10.1007/978-1-59745-521-3_23] [PMID: 19513686]
[19]
Varum, S.; Rodrigues, A.S.; Moura, M.B.; Momcilovic, O.; Easley, C.A., IV; Ramalho-Santos, J.; Van Houten, B.; Schatten, G. Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PLoS One, 2011, 6(6), e20914.
[http://dx.doi.org/10.1371/journal.pone.0020914] [PMID: 21698063]
[20]
Saiselet, M.; Floor, S.; Tarabichi, M.; Dom, G.; Hébrant, A.; van Staveren, W.C.; Maenhaut, C. Thyroid cancer cell lines: an overview. Front. Endocrinol. (Lausanne), 2012, 3, 133.
[http://dx.doi.org/10.3389/fendo.2012.00133] [PMID: 23162534]
[21]
Landa, I.; Pozdeyev, N.; Korch, C.; Marlow, L.A.; Smallridge, R.C.; Copland, J.A.; Henderson, Y.C.; Lai, S.Y.; Clayman, G.L.; Onoda, N.; Tan, A.C.; Garcia-Rendueles, M.E.R.; Knauf, J.A.; Haugen, B.R.; Fagin, J.A.; Schweppe, R.E. Comprehensive genetic characterization of human thyroid cancer cell lines: A validated panel for preclinical studies. Clin. Cancer Res., 2019, 25(10), 3141-3151.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-2953] [PMID: 30737244]
[22]
Wu, L.L.; Chiou, C.C.; Chang, P.Y.; Wu, J.T. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, athero-sclerosis and diabetics. Clin. Chim. Acta, 2004, 339(1-2), 1-9.
[http://dx.doi.org/10.1016/j.cccn.2003.09.010] [PMID: 14687888]
[23]
Chandel, N.S.; Schumacker, P.T. Cells depleted of mitochondrial DNA (rho0) yield insight into physiological mechanisms. FEBS Lett., 1999, 454(3), 173-176.
[http://dx.doi.org/10.1016/S0014-5793(99)00783-8] [PMID: 10431801]
[24]
Cork, G.K.; Thompson, J.; Slawson, C. Real Talk: The inter-play between the mTOR, AMPK, and hexosamine biosynthetic pathways in cell signaling. Front. Endocrinol. (Lausanne), 2018, 9, 522.
[http://dx.doi.org/10.3389/fendo.2018.00522] [PMID: 30237786]
[25]
Markowska, A.; Kaysiewicz, J.; Markowska, J. Huczyski, A. Doxycycline, salinomycin, monensin and ivermectin repositioned as can-cer drugs. Bioorg. Med. Chem. Lett., 2019, 29(13), 1549-1554.
[http://dx.doi.org/10.1016/j.bmcl.2019.04.045] [PMID: 31054863]
[26]
Joseph, M.M.; Aravind, S.R.; George, S.K.; Varghese, S.; Sreelekha, T.T. A galactomannan polysaccharide from Punica granatum imparts in vitro and in vivo anticancer activity. Carbohydr. Polym., 2013, 98(2), 1466-1475.
[http://dx.doi.org/10.1016/j.carbpol.2013.07.023] [PMID: 24053828]
[27]
Arya, J.S.; Joseph, M.M.; Sherin, D.R.; Nair, J.B.; Manojkumar, T.K.; Maiti, K.K. Exploring mitochondria-mediated intrinsic apoptosis by new phytochemical entities: an explicit observation of cytochrome c dynamics on lung and melanoma cancer cells. J. Med. Chem., 2019, 62(17), 8311-8329.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01098] [PMID: 31393121]
[28]
Mollenhauer, H.H.; Morré, D.J.; Rowe, L.D. Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity. Biochim. Biophys. Acta, 1990, 1031(2), 225-246.
[http://dx.doi.org/10.1016/0304-4157(90)90008-Z] [PMID: 2160275]
[29]
Souza, A.C.; Machado, F.S.; Celes, M.R.; Faria, G.; Rocha, L.B.; Silva, J.S.; Rossi, M.A. Mitochondrial damage as an early event of monensin-induced cell injury in cultured fibroblasts L929. J. Vet. Med. A Physiol. Pathol. Clin. Med., 2005, 52(5), 230-237.
[http://dx.doi.org/10.1111/j.1439-0442.2005.00728.x] [PMID: 15943607]
[30]
Johnson, J.M.; Lai, S.Y.; Cotzia, P.; Cognetti, D.; Luginbuhl, A.; Pribitkin, E.A.; Zhan, T.; Mollaee, M.; Domingo-Vidal, M.; Chen, Y.; Campling, B.; Bar-Ad, V.; Birbe, R.; Tuluc, M.; Martinez Outschoorn, U.; Curry, J. Mitochondrial metabolism as a treatment target in ana-plastic thyroid cancer. Semin. Oncol., 2015, 42(6), 915-922.
[http://dx.doi.org/10.1053/j.seminoncol.2015.09.025] [PMID: 26615136]
[31]
Skrti M.; Sriskanthadevan, S.; Jhas, B.; Gebbia, M.; Wang, X.; Wang, Z.; Hurren, R.; Jitkova, Y.; Gronda, M.; Maclean, N.; Lai, C.K.; Eberhard, Y.; Bartoszko, J.; Spagnuolo, P.; Rutledge, A.C.; Datti, A.; Ketela, T.; Moffat, J.; Robinson, B.H.; Cameron, J.H.; Wrana, J.; Eaves, C.J.; Minden, M.D.; Wang, J.C.; Dick, J.E.; Humphries, K.; Nislow, C.; Giaever, G.; Schimmer, A.D. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell, 2011, 20(5), 674-688.
[http://dx.doi.org/10.1016/j.ccr.2011.10.015] [PMID: 22094260]
[32]
Wang, B.; Ao, J.; Yu, D.; Rao, T.; Ruan, Y.; Yao, X. Inhibition of mitochondrial translation effectively sensitizes renal cell carcinoma to chemotherapy. Biochem. Biophys. Res. Commun., 2017, 490(3), 767-773.
[http://dx.doi.org/10.1016/j.bbrc.2017.06.115] [PMID: 28645610]
[33]
D’Andrea, A.; Gritti, I.; Nicoli, P.; Giorgio, M.; Doni, M.; Conti, A.; Bianchi, V.; Casoli, L.; Sabò, A.; Mironov, A.; Beznoussenko, G.V.; Amati, B. The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas. Oncotarget, 2016, 7(45), 72415-72430.
[http://dx.doi.org/10.18632/oncotarget.11719] [PMID: 27635472]
[34]
Xin, H.; Li, J.; Zhang, H.; Li, Y.; Zeng, S.; Wang, Z.; Zhang, Z.; Deng, F. Monensin may inhibit melanoma by regulating the selection be-tween differentiation and stemness of melanoma stem cells. PeerJ, 2019, 7, e7354.
[http://dx.doi.org/10.7717/peerj.7354] [PMID: 31380151]
[35]
Wang, X.; Wu, X.; Zhang, Z.; Ma, C.; Wu, T.; Tang, S.; Zeng, Z.; Huang, S.; Gong, C.; Yuan, C.; Zhang, L.; Feng, Y.; Huang, B.; Liu, W.; Zhang, B.; Shen, Y.; Luo, W.; Wang, X.; Liu, B.; Lei, Y.; Ye, Z.; Zhao, L.; Cao, D.; Yang, L.; Chen, X.; Haydon, R.C.; Luu, H.H.; Peng, B.; Liu, X.; He, T.C. Monensin inhibits cell proliferation and tumor growth of chemo-resistant pancreatic cancer cells by targeting the EGFR signaling pathway. Sci. Rep., 2018, 8(1), 17914.
[http://dx.doi.org/10.1038/s41598-018-36214-5] [PMID: 30559409]
[36]
Yusenko, M.V.; Trentmann, A.; Andersson, M.K.; Ghani, L.A.; Jakobs, A.; Arteaga Paz, M.F.; Mikesch, J.H.; Peter von Kries, J.; Sten-man, G.; Klempnauer, K.H. Monensin, a novel potent MYB inhibitor, suppresses proliferation of acute myeloid leukemia and adenoid cystic carcinoma cells. Cancer Lett., 2020, 479, 61-70.
[http://dx.doi.org/10.1016/j.canlet.2020.01.039] [PMID: 32014461]
[37]
Nair, J.B.; Joseph, M.M.; Arya, J.S.; Sreedevi, P.; Sujai, P.T.; Maiti, K.K. Elucidating a thermoresponsive multimodal photo-chemotherapeutic nanodelivery vehicle to overcome the barriers of doxorubicin therapy. ACS Appl. Mater. Interfaces, 2020, 12(39), 43365-43379.
[http://dx.doi.org/10.1021/acsami.0c08762] [PMID: 32880178]

Rights & Permissions Print Cite
Article Metrics
60
1
© 2024 Bentham Science Publishers | Privacy Policy