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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Inactivation of PDH can Reduce Anaplastic Thyroid Cancer Cells’ Sensitivity to Artemisinin

Author(s): Yitian Li*

Volume 22, Issue 9, 2022

Published on: 03 January, 2022

Page: [1753 - 1760] Pages: 8

DOI: 10.2174/1871520621666210910100803

Price: $65

Abstract

Background: Anaplastic Thyroid Cancer (ATC) is a rare subtype of thyroid tumors with a high mortality rate. Targeted therapies against ATC are ineffective and mostly transient. Artemisinin has shown excellent anti-tumor activity in several cancers, but its effects on ATC are still unknown.

Objective: To evaluate the effects of artemisinin on ATC cells and assess the mechanism underlying drug resistance.

Methods: The viability and proliferation rates of the artemisinin-treated CAL-62 and BHT-101 cells were analyzed by MTT and EdU incorporation assays. The protein expression levels were determined by Tandem Mass Tag (TMT) labeling quantitative proteomics and western blotting.

Results: Artemisinin treatment significantly decreased the expression levels of COX2 and COX7A2 and increased that of COX14, YEM1l1, ALAS1, and OAT after 48h. In addition, FTL was upregulated in the CAL-62 cells and downregulated in BHT-101 cells. The CAL-62 cells showed transient and reversible resistance to artemisinin, which was correlated to time-dependent changes in HIF1α, PDK1, and PDHA levels.

Conclusion: Artemisinin targets the mitochondrial respiratory chain proteins in ATC cells. CAL-62 cells show transient resistance to artemisinin via PDH downregulation, indicating that PDH activation may enhance the cytotoxic effects of artemisinin on ATC cells.

Keywords: Anaplastic thyroid cancer, artemisinin, tolerance, oxidative phosphorylation, HIF1α, PDK1.

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[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin., 2020, 70(1), 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[2]
Limaiem, F.; Kashyap, S.; Giwa, A.O. Anaplastic thyroid cancer. In: StatPearls; StatPearls publishing: treasure island (FL), 2020.
[3]
Cabanillas, M.E.; McFadden, D.G.; Durante, C. Thyroid cancer. Lancet, 2016, 388(10061), 2783-2795.
[http://dx.doi.org/10.1016/S0140-6736(16)30172-6] [PMID: 27240885]
[4]
Pozdeyev, N.; Rose, M.M.; Bowles, D.W.; Schweppe, R.E. Molecular therapeutics for anaplastic thyroid cancer. Semin. Cancer Biol., 2020, 61, 23-29.
[http://dx.doi.org/10.1016/j.semcancer.2020.01.005] [PMID: 31991166]
[5]
Ma, M.; Lin, B.; Wang, M.; Liang, X.; Su, L.; Okose, O.; Lv, W.; Li, J. Immunotherapy in anaplastic thyroid cancer. Am. J. Transl. Res., 2020, 12(3), 974-988.
[PMID: 32269728]
[6]
Efferth, T.; Dunstan, H.; Sauerbrey, A.; Miyachi, H.; Chitambar, C.R. The anti-malarial artesunate is also active against cancer. Int. J. Oncol., 2001, 18(4), 767-773.
[http://dx.doi.org/10.3892/ijo.18.4.767] [PMID: 11251172]
[7]
Woerdenbag, H.J.; Moskal, T.A.; Pras, N.; Malingré, T.M.
El-Feraly, F.S.; Kampinga, H.H.; Konings, A.W. Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J. Nat. Prod., 1993, 56(6), 849-856.
[http://dx.doi.org/10.1021/np50096a007] [PMID: 8350087]
[8]
Lai, H.; Singh, N.P. Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin. Cancer Lett., 1995, 91(1), 41-46.
[http://dx.doi.org/10.1016/0304-3835(94)03716-V] [PMID: 7750093]
[9]
Efferth, T.; Benakis, A.; Romero, M.R.; Tomicic, M.; Rauh, R.; Steinbach, D.; Häfer, R.; Stamminger, T.; Oesch, F.; Kaina, B.; Marschall, M. Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Free Radic. Biol. Med., 2004, 37(7), 998-1009.
[http://dx.doi.org/10.1016/j.freeradbiomed.2004.06.023] [PMID: 15336316]
[10]
Lai, H.; Sasaki, T.; Singh, N.P. Targeted treatment of cancer with artemisinin and artemisinin-tagged iron-carrying compounds. Expert Opin. Ther. Targets, 2005, 9(5), 995-1007.
[http://dx.doi.org/10.1517/14728222.9.5.995] [PMID: 16185154]
[11]
Huang, X.J.; Ma, Z.Q.; Zhang, W.P.; Lu, Y.B.; Wei, E.Q. Dihydroartemisinin exerts cytotoxic effects and inhibits hypoxia inducible factor-1alpha activation in C6 glioma cells. J. Pharm. Pharmacol., 2007, 59(6), 849-856.
[http://dx.doi.org/10.1211/jpp.59.6.0011] [PMID: 17637177]
[12]
Li, Z.; Li, Q.; Wu, J.; Wang, M.; Yu, J. Artemisinin and its derivatives as a repurposing anticancer agent: What else do we need to do? Molecules, 2016, 21(10), E1331.
[http://dx.doi.org/10.3390/molecules21101331] [PMID: 27739410]
[13]
Crespo-Ortiz, M.P.; Wei, M.Q. Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug. J. Biomed. Biotechnol., 2012, 2012, 247597.
[http://dx.doi.org/10.1155/2012/247597] [PMID: 22174561]
[14]
Efferth, T.; Sauerbrey, A.; Olbrich, A.; Gebhart, E.; Rauch, P.; Weber, H.O.; Hengstler, J.G.; Halatsch, M.E.; Volm, M.; Tew, K.D.; Ross, D.D.; Funk, J.O. Molecular modes of action of artesunate in tumor cell lines. Mol. Pharmacol., 2003, 64(2), 382-394.
[http://dx.doi.org/10.1124/mol.64.2.382] [PMID: 12869643]
[15]
Icard, P.; Kafara, P.; Steyaert, J.M.; Schwartz, L.; Lincet, H. The metabolic cooperation between cells in solid cancer tumors. Biochim. Biophys. Acta, 2014, 1846(1), 216-225.
[PMID: 24983675]
[16]
Solaini, G.; Sgarbi, G.; Baracca, A. Oxidative phosphorylation in cancer cells. Biochim. Biophys. Acta, 2011, 1807(6), 534-542.
[http://dx.doi.org/10.1016/j.bbabio.2010.09.003] [PMID: 20849810]
[17]
Villalba, M.; Rathore, M.G.; Lopez-Royuela, N.; Krzywinska, E.; Garaude, J.; Allende-Vega, N. From tumor cell metabolism to tumor immune escape. Int. J. Biochem. Cell Biol., 2013, 45(1), 106-113.
[http://dx.doi.org/10.1016/j.biocel.2012.04.024] [PMID: 22568930]
[18]
Kelloff, G.J.; Hoffman, J.M.; Johnson, B.; Scher, H.I.; Siegel, B.A.; Cheng, E.Y.; Cheson, B.D.; O’shaughnessy, J.; Guyton, K.Z.; Mankoff, D.A.; Shankar, L.; Larson, S.M.; Sigman, C.C.; Schilsky, R.L.; Sullivan, D.C. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin. Cancer Res., 2005, 11(8), 2785-2808.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-2626] [PMID: 15837727]
[19]
Bhattacharya, B.; Mohd Omar, M.F.; Soong, R. The Warburg effect and drug resistance. Br. J. Pharmacol., 2016, 173(6), 970-979.
[http://dx.doi.org/10.1111/bph.13422] [PMID: 26750865]
[20]
Denko, N.C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer, 2008, 8(9), 705-713.
[http://dx.doi.org/10.1038/nrc2468] [PMID: 19143055]
[21]
Nogueira, V.; Park, Y.; Chen, C.C.; Xu, P.Z.; Chen, M.L.; Tonic, I.; Unterman, T.; Hay, N. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell, 2008, 14(6), 458-470.
[http://dx.doi.org/10.1016/j.ccr.2008.11.003] [PMID: 19061837]
[22]
Baldini, E.; Tuccilli, C.; Prinzi, N.; Sorrenti, S.; Antonelli, A.; Gnessi, L.; Morrone, S.; Moretti, C.; Bononi, M.; Arlot-Bonnemains, Y.; D’Armiento, M.; Ulisse, S. Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines. Endocr. Relat. Cancer, 2014, 21(5), 797-811.
[http://dx.doi.org/10.1530/ERC-14-0299] [PMID: 25074669]
[23]
Li, Y.T.; Tian, X.T.; Wu, M.L.; Zheng, X.; Kong, Q.Y.; Cheng, X.X.; Zhu, G.W.; Liu, J.; Li, H. Resveratrol suppresses the growth and enhances retinoic acid sensitivity of anaplastic thyroid cancer cells. Int. J. Mol. Sci., 2018, 19(4), E1030.
[http://dx.doi.org/10.3390/ijms19041030] [PMID: 29596381]
[24]
Krishnamurthy, S.; Cerulli-Switzer, J.; Chapman, N.; Krishnamurthy, G.T. Comparison of gallbladder function obtained with regular CCK-8 and pharmacy-compounded CCK-8. J. Nucl. Med., 2003, 44(4), 499-504.
[PMID: 12679391]
[25]
Peng, F.; Wu, H.; Zheng, Y.; Xu, X.; Yu, J. The effect of noncoherent red light irradiation on proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. Lasers Med. Sci., 2012, 27(3), 645-653.
[http://dx.doi.org/10.1007/s10103-011-1005-z] [PMID: 22016038]
[26]
Klopfenstein, D.V.; Zhang, L.; Pedersen, B.S.; Ramírez, F.; Warwick Vesztrocy, A.; Naldi, A.; Mungall, C.J.; Yunes, J.M.; Botvinnik, O.; Weigel, M.; Dampier, W.; Dessimoz, C.; Flick, P.; Tang, H. GOATOOLS: A python library for gene ontology analyses. Sci. Rep., 2018, 8(1), 10872.
[http://dx.doi.org/10.1038/s41598-018-28948-z] [PMID: 30022098]
[27]
Xie, C.; Mao, X.; Huang, J.; Ding, Y.; Wu, J.; Dong, S.; Kong, L.; Gao, G.; Li, C.Y.; Wei, L. KOBAS 2.0: A web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res., 2011, 39, W316-22.
[28]
Wellen, K.E.; Thompson, C.B. A two-way street: reciprocal regulation of metabolism and signalling. Nat. Rev. Mol. Cell Biol., 2012, 13(4), 270-276.
[http://dx.doi.org/10.1038/nrm3305] [PMID: 22395772]
[29]
Flier, J.S.; Mueckler, M.M.; Usher, P.; Lodish, H.F. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Sci., 1987, 235(4795), 1492-1495.
[http://dx.doi.org/10.1126/science.3103217] [PMID: 3103217]
[30]
Birnbaum, M.J.; Haspel, H.C.; Rosen, O.M. Transformation of rat fibroblasts by FSV rapidly increases glucose transporter gene transcription. Sci., 1987, 235(4795), 1495-1498.
[http://dx.doi.org/10.1126/science.3029870] [PMID: 3029870]
[31]
Carracedo, A.; Cantley, L.C.; Pandolfi, P.P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer, 2013, 13(4), 227-232.
[http://dx.doi.org/10.1038/nrc3483] [PMID: 23446547]
[32]
Birsoy, K.; Wang, T.; Chen, W.W.; Freinkman, E.; Abu-Remaileh, M.; Sabatini, D.M. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell, 2015, 162(3), 540-551.
[http://dx.doi.org/10.1016/j.cell.2015.07.016] [PMID: 26232224]
[33]
Flaveny, C.A.; Griffett, K. El-Gendy, Bel-D.; Kazantzis, M.; Sengupta, M.; Amelio, A.L.; Chatterjee, A.; Walker, J.; Solt, L.A.; Kamenecka, T.M.; Burris, T.P. Broad anti-tumor activity of a small molecule that selectively targets the warburg effect and lipogenesis. Cancer Cell, 2015, 28(1), 42-56.
[http://dx.doi.org/10.1016/j.ccell.2015.05.007] [PMID: 26120082]
[34]
Sullivan, L.B.; Gui, D.Y.; Hosios, A.M.; Bush, L.N.; Freinkman, E.; Vander Heiden, M.G. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell, 2015, 162(3), 552-563.
[http://dx.doi.org/10.1016/j.cell.2015.07.017] [PMID: 26232225]
[35]
Qiu, H.Y.; Wang, P.F.; Li, Z.; Ma, J.T.; Wang, X.M.; Yang, Y.H.; Zhu, H.L. Synthesis of dihydropyrazole sulphonamide derivatives that act as anti-cancer agents through COX-2 inhibition. Pharmacol. Res., 2016, 104, 86-96.
[http://dx.doi.org/10.1016/j.phrs.2015.12.025] [PMID: 26723906]
[36]
Li, F.; Zhu, Y.T. HGF-activated colonic fibroblasts mediates carcinogenesis of colonic epithelial cancer cells via PKC-cMET-ERK1/2-COX-2 signaling. Cell. Signal., 2015, 27(4), 860-866.
[http://dx.doi.org/10.1016/j.cellsig.2015.01.014] [PMID: 25643632]
[37]
Hashemi Goradel, N.; Najafi, M.; Salehi, E.; Farhood, B.; Mortezaee, K. Cyclooxygenase-2 in cancer: A review. J. Cell. Physiol., 2019, 234(5), 5683-5699.
[http://dx.doi.org/10.1002/jcp.27411] [PMID: 30341914]
[38]
You, K.R.; Wen, J.; Lee, S.T.; Kim, D.G. Cytochrome c oxidase subunit III: a molecular marker for N-(4-hydroxyphenyl)retinamise-induced oxidative stress in hepatoma cells. J. Biol. Chem., 2002, 277(6), 3870-3877.
[http://dx.doi.org/10.1074/jbc.M109284200] [PMID: 11698412]
[39]
Slapke, J.; Schewe, T.; Hummel, S.; Winkler, J.; Kopf, M. Lung strips from guinea pigs as test system for lipoxygenase inhibitors. Inhibition of arachidonic acid-induced contractions by 3-t-butyl-4-hydroxyanisole and nordihydroguaiaretic acid. Biomed. Biochim. Acta, 1983, 42(10), 1309-1318.
[PMID: 6426477]
[40]
Hilf, R. Mitochondria are targets of photodynamic therapy. J. Bioenerg. Biomembr., 2007, 39(1), 85-89.
[http://dx.doi.org/10.1007/s10863-006-9064-8] [PMID: 17334915]
[41]
Biasutto, L.; Mattarei, A.; Marotta, E.; Bradaschia, A.; Sassi, N.; Garbisa, S.; Zoratti, M.; Paradisi, C. Development of mitochondria-targeted derivatives of resveratrol. Bioorg. Med. Chem. Lett., 2008, 18(20), 5594-5597.
[http://dx.doi.org/10.1016/j.bmcl.2008.08.100] [PMID: 18823777]
[42]
Asayama, S.; Kawamura, E.; Nagaoka, S.; Kawakami, H. Design of manganese porphyrin modified with mitochondrial signal peptide for a new antioxidant. Mol. Pharm., 2006, 3(4), 468-470.
[http://dx.doi.org/10.1021/mp0500667] [PMID: 16889441]
[43]
Cuchelkar, V.; Kopecková, P.; Kopecek, J. Novel HPMA copolymer-bound constructs for combined tumor and mitochondrial targeting. Mol. Pharm., 2008, 5(5), 776-786.
[http://dx.doi.org/10.1021/mp800019g] [PMID: 18767867]
[44]
Rainbolt, T.K.; Lebeau, J.; Puchades, C.; Wiseman, R.L. Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress. Cell Rep., 2016, 14(9), 2041-2049.
[http://dx.doi.org/10.1016/j.celrep.2016.02.011] [PMID: 26923599]
[45]
Shi, H.; Rampello, A.J.; Glynn, S.E.; Engineered, A.A.A. Engineered AAA+ proteases reveal principles of proteolysis at the mitochondrial inner membrane. Nat. Commun., 2016, 7, 13301.
[http://dx.doi.org/10.1038/ncomms13301] [PMID: 27786171]
[46]
Guillery, O.; Malka, F.; Landes, T.; Guillou, E.; Blackstone, C.; Lombès, A.; Belenguer, P.; Arnoult, D.; Rojo, M. Metalloprotease-mediated OPA1 processing is modulated by the mitochondrial membrane potential. Biol. Cell, 2008, 100(5), 315-325.
[http://dx.doi.org/10.1042/BC20070110] [PMID: 18076378]
[47]
Hartmann, B.; Wai, T.; Hu, H.; MacVicar, T.; Musante, L.; Fischer-Zirnsak, B.; Stenzel, W.; Gräf, R.; van den Heuvel, L.; Ropers, H.H.; Wienker, T.F.; Hübner, C.; Langer, T.; Kaindl, A.M. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. eLife, 2016, 5, 5.
[http://dx.doi.org/10.7554/eLife.16078] [PMID: 27495975]
[48]
Srinivasainagendra, V.; Sandel, M.W.; Singh, B.; Sundaresan, A.; Mooga, V.P.; Bajpai, P.; Tiwari, H.K.; Singh, K.K. Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma. Genome Med., 2017, 9(1), 31.
[http://dx.doi.org/10.1186/s13073-017-0420-6] [PMID: 28356157]
[49]
Herzfeld, A.; Knox, W.E. The properties, developmental formation, and estrogen induction of ornithine aminotransferase in rat tissues. J. Biol. Chem., 1968, 243(12), 3327-3332.
[http://dx.doi.org/10.1016/S0021-9258(18)93310-7] [PMID: 4298129]
[50]
Peraino, C.; Bunville, L.G.; Tahmisian, T.N. Chemical, physical, and morphological properties of ornithine Aminotransferase from rat liver. J. Biol. Chem., 1969, 244(9), 2241-2249.
[http://dx.doi.org/10.1016/S0021-9258(19)78217-9] [PMID: 5783831]
[51]
Seiler, N. Ornithine aminotransferase as a therapeutic target in hyperammonemias. Adv. Exp. Med. Biol., 1997, 420, 113-142.
[http://dx.doi.org/10.1007/978-1-4615-5945-0_8] [PMID: 9286430]
[52]
Seiler, N. Ornithine aminotransferase, a potential target for the treatment of hyperammonemias. Curr. Drug Targets, 2000, 1(2), 119-153.
[http://dx.doi.org/10.2174/1389450003349254] [PMID: 11465067]
[53]
Wang, G.; Shang, L.; Burgett, A.W.; Harran, P.G.; Wang, X. Diazonamide toxins reveal an unexpected function for ornithine delta-amino transferase in mitotic cell division. Proc. Natl. Acad. Sci. USA, 2007, 104(7), 2068-2073.
[http://dx.doi.org/10.1073/pnas.0610832104] [PMID: 17287350]
[54]
O’Donnell, J.J.; Sandman, R.P.; Martin, S.R. Gyrate atrophy of the retina: inborn error of L-ornithin:2-oxoacid aminotransferase. Science, 1978, 200(4338), 200-201.
[http://dx.doi.org/10.1126/science.635581] [PMID: 635581]
[55]
Shih, V.E.; Berson, E.L.; Mandell, R.; Schmidt, S.Y. Ornithine ketoacid transaminase deficiency in gyrate atrophy of the choroid and retina. Am. J. Hum. Genet., 1978, 30(2), 174-179.
[PMID: 655164]
[56]
Ueda, M.; Masu, Y.; Ando, A.; Maeda, H.; Del Monte, M.A.; Uyama, M.; Ito, S. Prevention of ornithine cytotoxicity by proline in human retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci., 1998, 39(5), 820-827.
[PMID: 9538890]
[57]
Tomiyama, A.; Serizawa, S.; Tachibana, K.; Sakurada, K.; Samejima, H.; Kuchino, Y.; Kitanaka, C. Critical role for mitochondrial oxidative phosphorylation in the activation of tumor suppressors Bax and Bak. J. Natl. Cancer Inst., 2006, 98(20), 1462-1473.
[http://dx.doi.org/10.1093/jnci/djj395] [PMID: 17047195]
[58]
Shen, Y.C.; Ou, D.L.; Hsu, C.; Lin, K.L.; Chang, C.Y.; Lin, C.Y.; Liu, S.H.; Cheng, A.L. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br. J. Cancer, 2006, 108(8), 72-81.
[http://dx.doi.org/10.1038/bjc.2012.559 ] [PMID: 23257894]

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