Abstract
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).
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.
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.
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.
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.
Graphical Abstract
[1]
Carling, T.; Udelsman, R. Thyroid Cancer. Annu. Rev. Med., 2014, 65(1), 125-137.
[http://dx.doi.org/10.1146/annurev-med-061512-105739] [PMID: 24274180]
[http://dx.doi.org/10.1146/annurev-med-061512-105739] [PMID: 24274180]
[2]
Asa, S.L.; Mete, O. Endocrine pathology: Past, present and future. Pathology, 2018, 50(1), 111-118.
[http://dx.doi.org/10.1016/j.pathol.2017.09.003] [PMID: 29132721]
[http://dx.doi.org/10.1016/j.pathol.2017.09.003] [PMID: 29132721]
[3]
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.
[http://dx.doi.org/10.1158/1055-9965.EPI-08-0960] [PMID: 19240234]
[http://dx.doi.org/10.1158/1055-9965.EPI-08-0960] [PMID: 19240234]
[4]
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.
[http://dx.doi.org/10.1089/thy.2009.1603] [PMID: 20001721]
[http://dx.doi.org/10.1089/thy.2009.1603] [PMID: 20001721]
[5]
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.
[http://dx.doi.org/10.1586/era.12.8] [PMID: 22369326]
[http://dx.doi.org/10.1586/era.12.8] [PMID: 22369326]
[6]
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.
[http://dx.doi.org/10.1210/jcem.86.4.7407] [PMID: 11297567]
[http://dx.doi.org/10.1210/jcem.86.4.7407] [PMID: 11297567]
[7]
Shaha, A.R. Implications of prognostic factors and risk groups in the management of differentiated thyroid cancer. Laryngoscope, 2004, 114(3), 393-402.
[http://dx.doi.org/10.1097/00005537-200403000-00001] [PMID: 15091208]
[http://dx.doi.org/10.1097/00005537-200403000-00001] [PMID: 15091208]
[8]
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.
[http://dx.doi.org/10.1530/ERC-18-0476] [PMID: 30615595]
[http://dx.doi.org/10.1530/ERC-18-0476] [PMID: 30615595]
[9]
Brieger, K.; Schiavone, S.; Miller, J., Jr; Krause, K.H. Reactive oxygen species: From health to disease. Swiss Med. Wkly., 2012, 142, w13659.
[http://dx.doi.org/10.4414/smw.2012.13659] [PMID: 22903797]
[http://dx.doi.org/10.4414/smw.2012.13659] [PMID: 22903797]
[10]
Chatterjee, A.; Dutta, C.P. Alkaloids of Piper longum Linn. I. Structure and synthesis of piperlongumine and piperlonguminine. Tetrahedron, 1967, 23(4), 1769-1781.
[http://dx.doi.org/10.1016/S0040-4020(01)82575-8] [PMID: 6047519]
[http://dx.doi.org/10.1016/S0040-4020(01)82575-8] [PMID: 6047519]
[11]
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.
[http://dx.doi.org/10.1080/01635581.2018.1445769] [PMID: 29543494]
[http://dx.doi.org/10.1080/01635581.2018.1445769] [PMID: 29543494]
[12]
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.
[http://dx.doi.org/10.1016/j.cellsig.2006.02.001] [PMID: 16531007]
[http://dx.doi.org/10.1016/j.cellsig.2006.02.001] [PMID: 16531007]
[13]
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.
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.10.056] [PMID: 16540388]
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.10.056] [PMID: 16540388]
[14]
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.
[http://dx.doi.org/10.1016/j.phrs.2020.104772] [PMID: 32283222]
[http://dx.doi.org/10.1016/j.phrs.2020.104772] [PMID: 32283222]
[15]
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.
[http://dx.doi.org/10.3892/ol.2015.3371] [PMID: 26622558]
[http://dx.doi.org/10.3892/ol.2015.3371] [PMID: 26622558]
[16]
Morales-Escobar, L.; Braca, A.; Pizza, C.; Tommasi, N.D. New phenolic derivatives from Vernonia mapirensis Gleason. ARKIVOC, 2007, 2007(7), 349-358.
[http://dx.doi.org/10.3998/ark.5550190.0008.731]
[http://dx.doi.org/10.3998/ark.5550190.0008.731]
[17]
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.
[http://dx.doi.org/10.1016/j.bse.2013.08.018]
[http://dx.doi.org/10.1016/j.bse.2013.08.018]
[18]
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.
[http://dx.doi.org/10.1371/journal.pone.0056643]
[http://dx.doi.org/10.1371/journal.pone.0056643]
[19]
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.
[http://dx.doi.org/10.1186/s13046-015-0266-y] [PMID: 26643256]
[http://dx.doi.org/10.1186/s13046-015-0266-y] [PMID: 26643256]
[20]
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.
[http://dx.doi.org/10.1155/2022/6268755] [PMID: 35222800]
[http://dx.doi.org/10.1155/2022/6268755] [PMID: 35222800]
[21]
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.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[22]
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.
[http://dx.doi.org/10.1002/jbt.22586] [PMID: 32711406]
[http://dx.doi.org/10.1002/jbt.22586] [PMID: 32711406]
[23]
Kasibhatla, S; Amarante-Mendes, GP; Finucane, D . Acridine Orange/
Ethidium Bromide (AO/EB) staining to detect apoptosis. CSH Protoc., 2006, 2006(3), pdb.prot4493..
[http://dx.doi.org/ 10.1101/pdb.prot4493]
[http://dx.doi.org/ 10.1101/pdb.prot4493]
[24]
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.
[http://dx.doi.org/10.1089/thy.1999.9.369] [PMID: 10319943]
[http://dx.doi.org/10.1089/thy.1999.9.369] [PMID: 10319943]
[25]
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.
[http://dx.doi.org/10.1186/1472-6882-13-166] [PMID: 23837445]
[http://dx.doi.org/10.1186/1472-6882-13-166] [PMID: 23837445]
[26]
Normile, D. Cell proliferation. Common control for cancer, stem cells. Science, 2002, 298(5600), 1869.
[http://dx.doi.org/10.1126/science.298.5600.1869] [PMID: 12471231]
[http://dx.doi.org/10.1126/science.298.5600.1869] [PMID: 12471231]
[27]
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.
[http://dx.doi.org/10.1007/s10620-017-4856-8] [PMID: 29197940]
[http://dx.doi.org/10.1007/s10620-017-4856-8] [PMID: 29197940]
[28]
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]
[PMID: 21959807]
[29]
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.
[http://dx.doi.org/10.1021/jo01264a035] [PMID: 5357533]
[http://dx.doi.org/10.1021/jo01264a035] [PMID: 5357533]
[30]
Sznarkowska, A.; Kostecka, A.; Meller, K.; Bielawski, K.P. Inhibition of cancer antioxidant defense by natural compounds. Oncotargeīt 1969, 34(12), 3908-3911.
[http://dx.doi.org/10.1021/jo01264a035]
[http://dx.doi.org/10.1021/jo01264a035]
[31]
Engel, R.H.; Evens, A.M. Oxidative stress and apoptosis: A new treatment paradigm in cancer. Front. Biosci., 2006, 11(1), 300-312.
[http://dx.doi.org/10.2741/1798] [PMID: 16146732]
[http://dx.doi.org/10.2741/1798] [PMID: 16146732]
[32]
Schieber, M.; Chandel, N.S. ROS function in redox signaling and oxidative stress. Curr. Biol., 2014, 24(10), R453-R462.
[http://dx.doi.org/10.1016/j.cub.2014.03.034] [PMID: 24845678]
[http://dx.doi.org/10.1016/j.cub.2014.03.034] [PMID: 24845678]
[33]
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.
[http://dx.doi.org/10.3390/ijms18071388] [PMID: 28661430]
[http://dx.doi.org/10.3390/ijms18071388] [PMID: 28661430]
[34]
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.
[http://dx.doi.org/10.1016/j.bbcan.2007.07.001] [PMID: 17693025]
[http://dx.doi.org/10.1016/j.bbcan.2007.07.001] [PMID: 17693025]
[35]
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.
[http://dx.doi.org/10.1002/jbt.22587] [PMID: 32726518]
[http://dx.doi.org/10.1002/jbt.22587] [PMID: 32726518]
[36]
Gogvadze, V.; Orrenius, S.; Zhivotovsky, B. Mitochondria in cancer cells: What is so special about them? Trends Cell Biol., 2008, 18(4), 165-173.
[http://dx.doi.org/10.1016/j.tcb.2008.01.006] [PMID: 18296052]
[http://dx.doi.org/10.1016/j.tcb.2008.01.006] [PMID: 18296052]
[37]
Chinnaiyan, A.M. The apoptosome: Heart and soul of the cell death machine. Neoplasia, 1999, 1(1), 5-15.
[http://dx.doi.org/10.1038/sj.neo.7900003] [PMID: 10935465]
[http://dx.doi.org/10.1038/sj.neo.7900003] [PMID: 10935465]
[38]
Liou, G.Y.; Storz, P. Reactive oxygen species in cancer. Free Radic. Res., 2010, 44(5), 479-496.
[http://dx.doi.org/10.3109/10715761003667554] [PMID: 20370557]
[http://dx.doi.org/10.3109/10715761003667554] [PMID: 20370557]
[39]
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.
[http://dx.doi.org/10.1089/jmf.2018.0008] [PMID: 29733262]
[http://dx.doi.org/10.1089/jmf.2018.0008] [PMID: 29733262]
[40]
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.
[http://dx.doi.org/10.1021/acs.jafc.8b07126] [PMID: 30688446]
[http://dx.doi.org/10.1021/acs.jafc.8b07126] [PMID: 30688446]
[41]
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.
[http://dx.doi.org/10.1038/sj.leu.2401043] [PMID: 9639410]
[http://dx.doi.org/10.1038/sj.leu.2401043] [PMID: 9639410]
Related Journals
Current Computer-Aided Drug Design
