Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Induction of Divergent Cell Death Pathways by Urea and Carbohydrazide Derivatives

Author(s): Sinem Yilmaz, Fatih Tok, Esra Atalay-Sahar, Bedia Kocyigit-Kaymakcioglu* and Petek Ballar-Kırmızıbayrak*

Volume 22, Issue 9, 2022

Published on: 06 January, 2022

Page: [1761 - 1768] Pages: 8

DOI: 10.2174/1871520621666210528153949

Price: $65

Abstract

Background: The complexity of cancer biology and the development of chemotherapy resistance are two main obstacles to cancer treatment and necessitate novel anticancer molecules that target different cell death pathways. Modulation of Endoplasmic Reticulum (ER) stress and subsequent activation of the Unfolded Protein Response (UPR) has been proposed as a potential chemotherapeutic target, as prolonged ER stress can lead to cell death via apoptosis or necrosis.

Objective: The present study aims to evaluate the molecular mechanism underlying the cytotoxic activity of selected urea and carbohydrazide derivatives.

Methods: Cell proliferation assays were performed on HeLa, Capan-1, MCF-7, HCC-1937, and MRC-5 cell lines by WST-1 assay. The expression levels of selected ER stress, autophagy, and apoptosis marker proteins were compared by immunoblotting to characterize the underlying mechanism of cytotoxicity. Flow cytometry was used to detect apoptosis.

Results: Of the tested cytotoxic compounds, 3a, 4a, 5a, 6a, and 1b dramatically and 5b moderately increased ER stress-related CHOP protein levels. Interestingly, 5b but not 3a, 4a, 5a, 6a, or 1b increased the expression of proapoptotic proteins such as cleaved PARP-1 and cleaved caspase-3 and -7. The flow-cytometry analysis further confirmed that the cytotoxic activity of 5b but not the other compounds is mediated by apoptosis, demonstrated by a significant increase in the percentage of late apoptotic cells (7-AAD/annexin V double-positive cells).

Conclusion: Our results suggest that changing a substituent from trifluoromethyl to nitro in urea and carbohydrazide core structure alters the cell death mechanism from apoptosis to an apoptosis-independent cell death pathway. This study shows an example of how such simple modifications of a core chemical structure could cause the induction of divergent cell death pathways.

Keywords: UPR, apoptosis, necrosis, cell death, CHOP, urea, carbohydrazide derivatives.

Graphical Abstract

[1]
Nagai, H.; Kim, Y.H. Cancer prevention from the perspective of global cancer burden patterns. J. Thorac. Dis., 2017, 9(3), 448-451.
[http://dx.doi.org/10.21037/jtd.2017.02.75] [PMID: 28449441]
[2]
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70.
[http://dx.doi.org/10.1016/S0092-8674(00)81683-9] [PMID: 10647931]
[3]
Fouad, Y.A.; Aanei, C. Revisiting the hallmarks of cancer. Am. J. Cancer Res., 2017, 7(5), 1016-1036.
[PMID: 28560055]
[4]
Ricci, M.S.; Zong, W.X. Chemotherapeutic approaches for targeting cell death pathways. Oncologist, 2006, 11(4), 342-357.
[http://dx.doi.org/10.1634/theoncologist.11-4-342] [PMID: 16614230]
[5]
Yadav, R.K.; Chae, S.W.; Kim, H.R.; Chae, H.J. Endoplasmic reticulum stress and cancer. J. Cancer Prev., 2014, 19(2), 75-88.
[http://dx.doi.org/10.15430/JCP.2014.19.2.75] [PMID: 25337575]
[6]
Corazzari, M.; Gagliardi, M.; Fimia, G.M.; Piacentini, M. Endoplasmic reticulum stress, unfolded protein response, and cancer cell fate. Front. Oncol., 2017, 7, 78.
[http://dx.doi.org/10.3389/fonc.2017.00078] [PMID: 28491820]
[7]
Ma, Y.M.; Peng, Y.M.; Zhu, Q.H.; Gao, A.H.; Chao, B.; He, Q.J.; Li, J.; Hu, Y.H.; Zhou, Y.B. Novel CHOP activator LGH00168 induces necroptosis in A549 human lung cancer cells via ROS-mediated ER stress and NF-κB inhibition. Acta Pharmacol. Sin., 2016, 37(10), 1381-1390.
[http://dx.doi.org/10.1038/aps.2016.61] [PMID: 27264312]
[8]
Nishitoh, H. CHOP is a multifunctional transcription factor in the ER stress response. J. Biochem., 2012, 151(3), 217-219.
[http://dx.doi.org/10.1093/jb/mvr143] [PMID: 22210905]
[9]
Han, J.; Back, S.H.; Hur, J.; Lin, Y.H.; Gildersleeve, R.; Shan, J.; Yuan, C.L.; Krokowski, D.; Wang, S.; Hatzoglou, M.; Kilberg, M.S.; Sartor, M.A.; Kaufman, R.J. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol., 2013, 15(5), 481-490.
[http://dx.doi.org/10.1038/ncb2738] [PMID: 23624402]
[10]
Wang, M.; Kaufman, R.J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature, 2016, 529(7586), 326-335.
[http://dx.doi.org/10.1038/nature17041] [PMID: 26791723]
[11]
Karakuş, S.; Tok, F.; Türk, S.; Şalva, E.; Tatar, G.; Taskın Tok, T. Kocyigit kaymakcıoglu, B. Synthesis, anticancer activity and ADMET studies of N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-[(3-substituted)ureido/thioureido] benzenesul- fonamide derivatives. Phosphorus Sulfur Silicon Relat. Elem., 2018, 193(8), 528-534.
[http://dx.doi.org/10.1080/10426507.2018.1452924]
[12]
Ribeiro de Souza, A.; Reig, M.; Bruix, J. Systemic treatment for advanced hepatocellular carcinoma: the search of new agents to join sorafenib in the effective therapeutic armamentarium. Expert Opin. Pharmacother., 2016, 17(14), 1923-1936.
[http://dx.doi.org/10.1080/14656566.2016.1225722] [PMID: 27598745]
[13]
Tok, F.; Koçyiğit-Kaymakçıoğlu, B.; İlhan, R.; Yılmaz, S.; Ballar-Kırmızıbayrak, P. Taskın- Tok, T. Design, synthesis, biological evaluation and molecular docking of novel molecules to PARP-1 enzyme. Turk. J. Chem., 2019, 43, 1290-1305.
[http://dx.doi.org/10.3906/kim-1905-15]
[14]
Chaitanya, G.V.; Steven, A.J.; Babu, P.P. PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun. Signal., 2010, 8, 31.
[http://dx.doi.org/10.1186/1478-811X-8-31] [PMID: 21176168]
[15]
Shi, Y. Caspase activation, inhibition, and reactivation: a mechanistic view. Protein Sci., 2004, 13(8), 1979-1987.
[http://dx.doi.org/10.1110/ps.04789804] [PMID: 15273300]
[16]
Wlodkowic, D.; Telford, W.; Skommer, J.; Darzynkiewicz, Z. Apoptosis and beyond: cytometry in studies of programmed cell death. Methods Cell Biol., 2011, 103, 55-98.
[http://dx.doi.org/10.1016/B978-0-12-385493-3.00004-8] [PMID: 21722800]
[17]
Bustos, P.L.; Volta, B.J.; Perrone, A.E.; Milduberger, N.; Bua, J. A homolog of cyclophilin D is expressed in Trypanosoma cruzi and is involved in the oxidative stress-damage response. Cell Death Discov., 2017, 3, 16092.
[http://dx.doi.org/10.1038/cddiscovery.2016.92] [PMID: 28179991]
[18]
Park, E.J.; Min, K-J.; Lee, T-J.; Yoo, Y-H.; Kim, Y-S.; Kwon, T.K. β-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells. Cell Death Dis., 2014, 5(5), e1230.
[http://dx.doi.org/10.1038/cddis.2014.202] [PMID: 24832602]
[19]
Shibuya, H.; Kato, Y.; Saito, M.; Isobe, T.; Tsuboi, R.; Koga, M.; Toyota, H.; Mizuguchi, J. Induction of apoptosis and/or necrosis following exposure to antitumour agents in a melanoma cell line, probably through modulation of Bcl-2 family proteins. Melanoma Res., 2003, 13(5), 457-464.
[http://dx.doi.org/10.1097/00008390-200310000-00004] [PMID: 14512787]
[20]
Yan, M.M.; Ni, J.D.; Song, D.; Ding, M.; Huang, J. Interplay between unfolded protein response and autophagy promotes tumor drug resistance. Oncol. Lett., 2015, 10(4), 1959-1969.
[http://dx.doi.org/10.3892/ol.2015.3508] [PMID: 26622781]
[21]
Johansen, T.; Lamark, T. Selective autophagy mediated by autophagic adapter proteins. Autophagy, 2011, 7(3), 279-296.
[http://dx.doi.org/10.4161/auto.7.3.14487] [PMID: 21189453]
[22]
B’chir, W.; Maurin, A.C.; Carraro, V.; Averous, J.; Jousse, C.; Muranishi, Y.; Parry, L.; Stepien, G.; Fafournoux, P.; Bruhat, A. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res., 2013, 41(16), 7683-7699.
[http://dx.doi.org/10.1093/nar/gkt563] [PMID: 23804767]
[23]
Rammohan, A.; Bhaskar, B.V.; Venkateswarlu, N.; Gu, W.; Zyryanov, G.V. Design, synthesis, docking and biological evaluation of chalcones as promising antidiabetic agents. Bioorg. Chem., 2020, 95, 103527.
[http://dx.doi.org/10.1016/j.bioorg.2019.103527] [PMID: 31911298]
[24]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[25]
Tait, S.W.; Ichim, G.; Green, D.R. Die another way--non-apoptotic mechanisms of cell death. J. Cell Sci., 2014, 127(Pt 10), 2135-2144.
[http://dx.doi.org/10.1242/jcs.093575] [PMID: 24833670]
[26]
Galluzzi, L.; Vitale, I.; Aaronson, S.A.; Abrams, J.M.; Adam, D.; Agostinis, P.; Alnemri, E.S.; Altucci, L.; Amelio, I.; Andrews, D.W.; Annicchiarico-Petruzzelli, M.; Antonov, A.V.; Arama, E.; Baehrecke, E.H.; Barlev, N.A.; Bazan, N.G.; Bernassola, F.; Bertrand, M.J.M.; Bianchi, K.; Blagosklonny, M.V.; Blomgren, K.; Borner, C.; Boya, P.; Brenner, C.; Campanella, M.; Candi, E.; Carmona-Gutierrez, D.; Cecconi, F.; Chan, F.K.; Chandel, N.S.; Cheng, E.H.; Chipuk, J.E.; Cidlowski, J.A.; Ciechanover, A.; Cohen, G.M.; Conrad, M.; Cubillos-Ruiz, J.R.; Czabotar, P.E.; D’Angiolella, V.; Dawson, T.M.; Dawson, V.L.; De Laurenzi, V.; De Maria, R.; Debatin, K.M.; DeBerardinis, R.J.; Deshmukh, M.; Di Daniele, N.; Di Virgilio, F.; Dixit, V.M.; Dixon, S.J.; Duckett, C.S.; Dynlacht, B.D.; El-Deiry, W.S.; Elrod, J.W.; Fimia, G.M.; Fulda, S.; García-Sáez, A.J.; Garg, A.D.; Garrido, C.; Gavathiotis, E.; Golstein, P.; Gottlieb, E.; Green, D.R.; Greene, L.A.; Gronemeyer, H.; Gross, A.; Hajnoczky, G.; Hardwick, J.M.; Harris, I.S.; Hengartner, M.O.; Hetz, C.; Ichijo, H.; Jäättelä, M.; Joseph, B.; Jost, P.J.; Juin, P.P.; Kaiser, W.J.; Karin, M.; Kaufmann, T.; Kepp, O.; Kimchi, A.; Kitsis, R.N.; Klionsky, D.J.; Knight, R.A.; Kumar, S.; Lee, S.W.; Lemasters, J.J.; Levine, B.; Linkermann, A.; Lipton, S.A.; Lockshin, R.A.; López-Otín, C.; Lowe, S.W.; Luedde, T.; Lugli, E.; MacFarlane, M.; Madeo, F.; Malewicz, M.; Malorni, W.; Manic, G.; Marine, J.C.; Martin, S.J.; Martinou, J.C.; Medema, J.P.; Mehlen, P.; Meier, P.; Melino, S.; Miao, E.A.; Molkentin, J.D.; Moll, U.M.; Muñoz-Pinedo, C.; Nagata, S.; Nuñez, G.; Oberst, A.; Oren, M.; Overholtzer, M.; Pagano, M.; Panaretakis, T.; Pasparakis, M.; Penninger, J.M.; Pereira, D.M.; Pervaiz, S.; Peter, M.E.; Piacentini, M.; Pinton, P.; Prehn, J.H.M.; Puthalakath, H.; Rabinovich, G.A.; Rehm, M.; Rizzuto, R.; Rodrigues, C.M.P.; Rubinsztein, D.C.; Rudel, T.; Ryan, K.M.; Sayan, E.; Scorrano, L.; Shao, F.; Shi, Y.; Silke, J.; Simon, H.U.; Sistigu, A.; Stockwell, B.R.; Strasser, A.; Szabadkai, G.; Tait, S.W.G.; Tang, D.; Tavernarakis, N.; Thorburn, A.; Tsujimoto, Y.; Turk, B.; Vanden Berghe, T.; Vandenabeele, P.; Vander Heiden, M.G.; Villunger, A.; Virgin, H.W.; Vousden, K.H.; Vucic, D.; Wagner, E.F.; Walczak, H.; Wallach, D.; Wang, Y.; Wells, J.A.; Wood, W.; Yuan, J.; Zakeri, Z.; Zhivotovsky, B.; Zitvogel, L.; Melino, G.; Kroemer, G. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ., 2018, 25(3), 486-541.
[http://dx.doi.org/10.1038/s41418-017-0012-4] [PMID: 29362479]
[27]
Vanlangenakker, N.; Vanden Berghe, T.; Vandenabeele, P. Many stimuli pull the necrotic trigger, an overview. Cell Death Differ., 2012, 19(1), 75-86.
[http://dx.doi.org/10.1038/cdd.2011.164] [PMID: 22075985]
[28]
Christofferson, D.E.; Yuan, J. Necroptosis as an alternative form of programmed cell death. Curr. Opin. Cell Biol., 2010, 22(2), 263-268.
[http://dx.doi.org/10.1016/j.ceb.2009.12.003] [PMID: 20045303]
[29]
Cirone, M.; Gilardini Montani, M.S.; Granato, M.; Garufi, A.; Faggioni, A.; D’Orazi, G. Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences. J. Exp. Clin. Cancer Res., 2019, 38(1), 262.
[http://dx.doi.org/10.1186/s13046-019-1275-z] [PMID: 31200739]
[30]
Shah, P.; Westwell, A.D. The role of fluorine in medicinal chemistry. J. Enzyme Inhib. Med. Chem., 2007, 22(5), 527-540.
[http://dx.doi.org/10.1080/14756360701425014] [PMID: 18035820]
[31]
Nepali, K.; Lee, H.Y.; Liou, J.P. Nitro-Group-Containing Drugs. J. Med. Chem., 2019, 26(6), 2851-2893.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00147] [PMID: 30295477]

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