<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE root>
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="research-article" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Combinatorial Chemistry &amp; High Throughput Screening</journal-id><journal-title-group><journal-title xml:lang="en">Combinatorial Chemistry &amp; High Throughput Screening</journal-title><trans-title-group xml:lang="ru"><trans-title>Combinatorial Chemistry &amp; High Throughput Screening</trans-title></trans-title-group></journal-title-group><issn publication-format="print">1386-2073</issn><issn publication-format="electronic">1875-5402</issn><publisher><publisher-name xml:lang="en">Bentham Science</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">644178</article-id><article-id pub-id-type="doi">10.2174/0113862073286226240220092357</article-id><article-categories><subj-group subj-group-type="toc-heading"><subject>Chemistry</subject></subj-group><subj-group subj-group-type="article-type"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title xml:lang="en">Vernodalin Triggers ROS-Mediated Apoptosis in TPC-1 Human Papillary Thyroid Cancer Cells via Suppression of the MAPKs Signaling Pathway</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Xijia</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><name><surname>Wei</surname><given-names>Meng</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff2"/></contrib><contrib contrib-type="author"><name><surname>An</surname><given-names>Yuan</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><name><surname>Liang</surname><given-names>Qinlong</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff4"/></contrib><contrib contrib-type="author"><name><surname>Nan</surname><given-names>Jing</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><name><surname>Vijayalakshmi</surname><given-names>Annamalai</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff5"/></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Zizhang</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff3"/></contrib></contrib-group><aff id="aff1"><institution>Department of General Surgery, Xi'an Gaoxin Hospital</institution></aff><aff id="aff2"><institution>Dialysis Department of Nephrology Hospital, The First Affiliated Hospital of Xian Jiaotong University</institution></aff><aff id="aff3"><institution>Department of Head and Neck Surgery, Shaanxi Provincial Tumor Hospital, The Affiliated Hospital of Xi'an Jiaotong Univesity</institution></aff><aff id="aff4"><institution>Department of Head and Neck Surgery, Shaanxi Provincial Tumor Hospital,, The Affiliated Hospital of Xi'an Jiaotong Univesity</institution></aff><aff id="aff5"><institution>, Galileovasan Offshore and Research And Development Pvt. Ltd</institution></aff><pub-date date-type="pub" iso-8601-date="2024-07-15" publication-format="electronic"><day>15</day><month>07</month><year>2024</year></pub-date><volume>27</volume><issue>14</issue><issue-title xml:lang="ru"/><fpage>2151</fpage><lpage>2158</lpage><history><date date-type="received" iso-8601-date="2025-01-07"><day>07</day><month>01</month><year>2025</year></date></history><permissions><copyright-statement xml:lang="en">Copyright ©; 2024, Bentham Science Publishers</copyright-statement><copyright-year>2024</copyright-year><copyright-holder xml:lang="en">Bentham Science Publishers</copyright-holder><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/"/></permissions><self-uri xlink:href="https://rjpbr.com/1386-2073/article/view/644178">https://rjpbr.com/1386-2073/article/view/644178</self-uri><abstract xml:lang="en"><p id="idm46041443783632">Background:Thyroid Cancer (TC) is an endocrine organ malignancy that has become more common in recent decades. Vernodalin (VN), a cytotoxic sesquiterpene, has been reported to exhibit anticancer properties against human breast and liver cancer cells. However, no study has explored the efficacy of VN with respect to its antiproliferative and apoptotic action on human Papillary Thyroid Cancer cells (PTC).</p><p id="idm46041443787632">Objective:The study intended to examine the antitumor and antiproliferative effects of VN and the apoptosis mechanisms underlying its action on TPC-1 human PTC cells.</p><p id="idm46041443791600">Methods:In this study, we examined the VN cell viability by MTT assay; performed ROS measurement by DCFH staining method, MMP identification by Rh-123 staining method, and apoptotic morphological assay by employing AO/EB and DAPI stain method, and further, p38 MAPK/ERK/JNK cell proliferation markers were determined by western blotting technique.</p><p id="idm46041443796656">Results:The findings showed that VN could inhibit the growth of PTC cells by increasing intracellular ROS, damaging MMP, and stimulating apoptosis in a concentration-dependent manner. The study demonstrated how VN inhibited TPC-1 cell viability by causing ROS-induced cell death via the MAPK signaling pathway.</p><p id="idm46041443806032">Conclusion:VN may serve as an agonist to impact apoptosis in PTC cells. In human PTC, VN could play an effective role in chemotherapy. More studies pertaining to animal tumor models are needed to prove its anti-cancer effectiveness in vivo.</p></abstract><kwd-group xml:lang="en"><kwd>Thyroid cancer</kwd><kwd>papillary thyroid cancer</kwd><kwd>vernodalin</kwd><kwd>apoptosis</kwd><kwd>MAPKs</kwd><kwd>DCFH staining method.</kwd></kwd-group></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>Carling, T.; Udelsman, R. Thyroid Cancer. Annu. Rev. Med., 2014, 65(1), 125-137. doi: 10.1146/annurev-med-061512-105739 PMID: 24274180</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>Asa, S.L.; Mete, O. Endocrine pathology: Past, present and future. Pathology, 2018, 50(1), 111-118. doi: 10.1016/j.pathol.2017.09.003 PMID: 29132721</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>Enewold, L.; Zhu, K.; Ron, E.; Marrogi, A.J.; Stojadinovic, A.; Peoples, G.E.; Devesa, S.S. Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980-2005. Cancer Epidemiol. Biomarkers Prev., 2009, 18(3), 784-791. doi: 10.1158/1055-9965.EPI-08-0960 PMID: 19240234</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>Schlumberger, M.; Sherman, S.I. Clinical trials for progressive differentiated thyroid cancer: Patient selection, study design, and recent advances. Thyroid, 2009, 19(12), 1393-1400. doi: 10.1089/thy.2009.1603 PMID: 20001721</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>Kojic, K.L.; Kojic, S.L.; Wiseman, S.M. Differentiated thyroid cancers: A comprehensive review of novel targeted therapies. Expert Rev. Anticancer Ther., 2012, 12(3), 345-357. doi: 10.1586/era.12.8 PMID: 22369326</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>Mazzaferri, E.L.; Kloos, R.T. Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer. J. Clin. Endocrinol. Metab., 2001, 86(4), 1447-1463. doi: 10.1210/jcem.86.4.7407 PMID: 11297567</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>Shaha, A.R. Implications of prognostic factors and risk groups in the management of differentiated thyroid cancer. Laryngoscope, 2004, 114(3), 393-402. doi: 10.1097/00005537-200403000-00001 PMID: 15091208</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>Ameziane El Hassani, R.; Buffet, C.; Leboulleux, S.; Dupuy, C.; Dupuy, C. Oxidative stress in thyroid carcinomas: Biological and clinical significance. Endocr. Relat. Cancer, 2019, 26(3), R131-R143. doi: 10.1530/ERC-18-0476 PMID: 30615595</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>Brieger, K.; Schiavone, S.; Miller, J., Jr; Krause, K.H. Reactive oxygen species: From health to disease. Swiss Med. Wkly., 2012, 142, w13659. doi: 10.4414/smw.2012.13659 PMID: 22903797</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>Chatterjee, A.; Dutta, C.P. Alkaloids of Piper longum Linn. I. Structure and synthesis of piperlongumine and piperlonguminine. Tetrahedron, 1967, 23(4), 1769-1781. doi: 10.1016/S0040-4020(01)82575-8 PMID: 6047519</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>Song, X.; Gao, T.; Lei, Q.; Zhang, L.; Yao, Y.; Xiong, J. Piperlongumine induces apoptosis in human melanoma cells via reactive oxygen species mediated mitochondria disruption. Nutr. Cancer, 2018, 70(3), 502-511. doi: 10.1080/01635581.2018.1445769 PMID: 29543494</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>Aggeli, I.K.S.; Gaitanaki, C.; Beis, I. Involvement of JNKs and p38-MAPK/MSK1 pathways in H2O2-induced upregulation of heme oxygenase-1 mRNA in H9c2 cells. Cell. Signal., 2006, 18(10), 1801-1812. doi: 10.1016/j.cellsig.2006.02.001 PMID: 16531007</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>Shen, H.M.; Liu, Z. JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radic. Biol. Med., 2006, 40(6), 928-939. doi: 10.1016/j.freeradbiomed.2005.10.056 PMID: 16540388</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>Tripathi, S.K.; Biswal, B.K. Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent. Pharmacol. Res., 2020, 156, 104772. doi: 10.1016/j.phrs.2020.104772 PMID: 32283222</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>Li, W.; Wen, C.; Bai, H.; Wang, X.; Zhang, X.; Huang, L.; Yang, X.; Iwamoto, A.; Liu, H. JNK signaling pathway is involved in piperlongumine-mediated apoptosis in human colorectal cancer HCT116 cells. Oncol. Lett., 2015, 10(2), 709-715. doi: 10.3892/ol.2015.3371 PMID: 26622558</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>Morales-Escobar, L.; Braca, A.; Pizza, C.; Tommasi, N.D. New phenolic derivatives from Vernonia mapirensis Gleason. ARKIVOC, 2007, 2007(7), 349-358. doi: 10.3998/ark.5550190.0008.731</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>Igual, M.O.; Martucci, M.E.P.; Da Costa, F.B.; Gobbo-Neto, L. Sesquiterpene lactones, chlorogenic acids and flavonoids from leaves of Vernonia polyanthes Less (Asteraceae). Biochem. Syst. Ecol., 2013, 51, 94-97. doi: 10.1016/j.bse.2013.08.018</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>Looi, CY.; Arya, A.; Cheah, FK. Induction of apoptosis in human breast cancer cells via caspase pathway by vernodalin isolated from Centratherum anthelminticum. PLoS One, 2013, 8(2), 56643. doi: 10.1371/journal.pone.0056643</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>Ananda Sadagopan, S.K.; Mohebali, N.; Looi, C.Y.; Hasanpourghadi, M.; Pandurangan, A.K.; Arya, A.; Karimian, H.; Mustafa, M.R. Forkhead box transcription factor (FOXO3a) mediates the cytotoxic effect of vernodalin in vitro and inhibits the breast tumor growth in vivo. J. Exp. Clin. Cancer Res., 2015, 34(1), 147. doi: 10.1186/s13046-015-0266-y PMID: 26643256</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>Orlandella, F.M.; Mirabelli, P.; De Stefano, A.E.; Iervolino, P.L.C.; Luciano, N.; DAngelo, S.; Salvatore, G. Effects of annurca flesh apple polyphenols in human thyroid cancer cell lines. Oxid. Med. Cell. Longev., 2022, 2022, 1-14. doi: 10.1155/2022/6268755 PMID: 35222800</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63. doi: 10.1016/0022-1759(83)90303-4 PMID: 6606682</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>Velu, P.; Vijayalakshmi, A.; Vinothkumar, V. Retracted: Syringic acid suppresses oral squamous cell carcinoma SCC131 cell proliferation via modulation of mitochondria-mediated apoptosis signaling pathways. J. Biochem. Mol. Toxicol., 2020, 34(12), e22586. doi: 10.1002/jbt.22586 PMID: 32711406</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>Kasibhatla, S; Amarante-Mendes, GP; Finucane, D . Acridine Orange/ Ethidium Bromide (AO/EB) staining to detect apoptosis. CSH Protoc., 2006, 2006(3), pdb.prot4493.. doi: 10.1101/pdb.prot4493</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>Yin, F.; Giuliano, A.; Van Herle, A.J. Growth inhibitory effects of flavonoids in human thyroid cancer cell lines. Thyroid, 1999, 9(4), 369-376. doi: 10.1089/thy.1999.9.369 PMID: 10319943</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>Looi, C.Y.; Moharram, B.; Paydar, M.; Wong, Y.L.; Leong, K.H.; Mohamad, K.; Arya, A.; Wong, W.F.; Mustafa, M.R. Induction of apoptosis in melanoma A375 cells by a chloroform fraction of Centratherum anthelminticum (L.) seeds involves NF-kappaB, p53 and Bcl-2-controlled mitochondrial signaling pathways. BMC Complement. Altern. Med., 2013, 13(1), 166. doi: 10.1186/1472-6882-13-166 PMID: 23837445</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>Normile, D. Cell proliferation. Common control for cancer, stem cells. Science, 2002, 298(5600), 1869. doi: 10.1126/science.298.5600.1869 PMID: 12471231</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>Hu, X.; Ma, J.; Vikash, V.; Li, J.; Wu, D.; Liu, Y.; Zhang, J.; Dong, W. Thymoquinone augments cisplatin-induced apoptosis on esophageal carcinoma through mitigating the activation of jak2/stat3 pathway. Dig. Dis. Sci., 2018, 63(1), 126-134. doi: 10.1007/s10620-017-4856-8 PMID: 29197940</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>Kasim, L.S.; Ferro, V.; Odukoya, O.A.; Ukpo, G.E.; Seidel, V.; Gray, A.I.; Waigh, R. Cytotoxicity of isolated compounds from the extracts of Struchium sparganophora (Linn) Ktze asteraceae. Pak. J. Pharm. Sci., 2011, 24(4), 475-478. PMID: 21959807</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>Kupchan, S.M.; Hemingway, R.J.; Karim, A.; Werner, D. Tumor inhibitors. XLVII. Vernodalin and vernomygdin, two new cytotoxic sesquiterpene lactones from Vernonia amygdalina del. J. Org. Chem., 1969, 34(12), 3908-3911. doi: 10.1021/jo01264a035 PMID: 5357533</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>Sznarkowska, A.; Kostecka, A.; Meller, K.; Bielawski, K.P. Inhibition of cancer antioxidant defense by natural compounds. Oncotargeīt 1969, 34(12), 3908-3911. doi: 10.1021/jo01264a035</mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation>Engel, R.H.; Evens, A.M. Oxidative stress and apoptosis: A new treatment paradigm in cancer. Front. Biosci., 2006, 11(1), 300-312. doi: 10.2741/1798 PMID: 16146732</mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation>Schieber, M.; Chandel, N.S. ROS function in redox signaling and oxidative stress. Curr. Biol., 2014, 24(10), R453-R462. doi: 10.1016/j.cub.2014.03.034 PMID: 24845678</mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation>Mühleisen, L.; Alev, M.; Unterweger, H.; Subatzus, D.; Pöttler, M.; Friedrich, R.; Alexiou, C.; Janko, C. Analysis of hypericin-mediated effects and implications for targeted photodynamic therapy. Int. J. Mol. Sci., 2017, 18(7), 1388. doi: 10.3390/ijms18071388 PMID: 28661430</mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation>Buytaert, E.; Dewaele, M.; Agostinis, P. Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. Biochim. Biophys. Acta Rev. Cancer, 2007, 1776(1), 86-107. doi: 10.1016/j.bbcan.2007.07.001 PMID: 17693025</mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation>Mohebali, N.; Pandurangan, A.K.; Mustafa, M.R.; Anandasadagopan, S.K.; Alagumuthu, T. Vernodalin induces apoptosis through the activation of ROS/JNK pathway in human colon cancer cells. J. Biochem. Mol. Toxicol., 2020, 34(12), e22587. doi: 10.1002/jbt.22587 PMID: 32726518</mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation>Gogvadze, V.; Orrenius, S.; Zhivotovsky, B. Mitochondria in cancer cells: What is so special about them? Trends Cell Biol., 2008, 18(4), 165-173. doi: 10.1016/j.tcb.2008.01.006 PMID: 18296052</mixed-citation></ref><ref id="B37"><label>37.</label><mixed-citation>Chinnaiyan, A.M. The apoptosome: Heart and soul of the cell death machine. Neoplasia, 1999, 1(1), 5-15. doi: 10.1038/sj.neo.7900003 PMID: 10935465</mixed-citation></ref><ref id="B38"><label>38.</label><mixed-citation>Liou, G.Y.; Storz, P. Reactive oxygen species in cancer. Free Radic. Res., 2010, 44(5), 479-496. doi: 10.3109/10715761003667554 PMID: 20370557</mixed-citation></ref><ref id="B39"><label>39.</label><mixed-citation>Smolensky, D.; Rhodes, D.; McVey, D.S.; Fawver, Z.; Perumal, R.; Herald, T.; Noronha, L. High-polyphenol sorghum bran extract inhibits cancer cell growth through ros induction, cell cycle arrest, and apoptosis. J. Med. Food, 2018, 21(10), 990-998. doi: 10.1089/jmf.2018.0008 PMID: 29733262</mixed-citation></ref><ref id="B40"><label>40.</label><mixed-citation>Wu, H.; Fu, X.; Cao, W.; Xiang, W.; Hou, Y.; Ma, J.; Wang, Y.; Fan, C. Induction of apoptosis in human glioma cells by fucoxanthin via triggering of ROS-mediated oxidative damage and regulation of MAPKs and PI3KAKT pathways. J. Agric. Food Chem., 2019, 67(8), 2212-2219. doi: 10.1021/acs.jafc.8b07126 PMID: 30688446</mixed-citation></ref><ref id="B41"><label>41.</label><mixed-citation>Drexler, H.G. Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemialymphoma cells. Leukemia, 1998, 12(6), 845-859. doi: 10.1038/sj.leu.2401043 PMID: 9639410</mixed-citation></ref></ref-list></back></article>
