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

Cytotoxic and Apoptotic Impacts of Ceranib-2 on RAW 264.7 Macrophage Cells

Author(s): filiz Susuz Alanyalı* and Osman Algı

Volume 23, Issue 20, 2023

Published on: 30 October, 2023

Page: [2183 - 2188] Pages: 6

DOI: 10.2174/1871520623666221116110823

Price: $65

Abstract

Background: Many ceramidase inhibitors have been developed and identified as potential treatment agents for various types of tumors in the last several decades. In recent years, their therapeutic potential against tumors has gained great attention. Inhibition of ceramidase is r eportedly related to apoptosis and cytotoxicity in macrophages, which are closely related to tumor development and progression. However, whether and how ceranib-2, a novel ceramidase inhibitor, can exert its cytotoxic and apoptotic effects on RAW 264.7, a macrophage cell line established from a tumor in a male mouse induced with the Abelson murine leukemia virus, remains unknown.

Objective: In this study, we aimed to investigate whether and how ceranib-2 can exert cytotoxic, antiproliferative, and apoptotic effects on the RAW264.7 macrophages.

Methods: We performed the MTT assay, Annexin V staining assay, and confocal microscopy to detect the cytotoxicity, apoptosis, and morphological changes, respectively, in the RAW264.7 cells.

Results: The viability of RAW264.7 cells treated with ceranib-2 was decreased as the doses of ceranib-2 increased at 24 h and 48 h due to apoptosis resulting from ceranib-2-reduced integrity of the mitochondrial membrane. Moreover, morphological changes were observed in these ceranib-2 exposed cells, further indicating the role of ceranib-2 in inducing apoptosis in these cells.

Conclusion: Ceranib-2 is cytotoxic to RAW 264.7 macrophages and can induce apoptosis in these cells.

« Previous Next »
Graphical Abstract

[1]
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]
[2]
Nakano, K.; Vousden, K.H. Puma, a novel proapoptotic gene, is induced by p53. Mol. Cell, 2001, 7(3), 683-694.
[http://dx.doi.org/10.1016/S1097-2765(01)00214-3] [PMID: 11463392]
[3]
Sa, G.; Das, T. Anti cancer effects of curcumin: Cycle of life and death. Cell Div., 2008, 3(1), 14.
[http://dx.doi.org/10.1186/1747-1028-3-14] [PMID: 18834508]
[4]
Ogretmen, B.; Hannun, Y.A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer, 2004, 4(8), 604-616.
[http://dx.doi.org/10.1038/nrc1411] [PMID: 15286740]
[5]
Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat. Rev. Cancer, 2018, 18(1), 33-50.
[http://dx.doi.org/10.1038/nrc.2017.96] [PMID: 29147025]
[6]
Radin, N.S. Killing cancer cells by poly-drug elevation of ceramide levels. Eur. J. Biochem., 2001, 268(2), 193-204.
[http://dx.doi.org/10.1046/j.1432-1033.2001.01845.x] [PMID: 11168352]
[7]
Senchenkov, A.; Litvak, D.A.; Cabot, M.C. Targeting ceramide metabolism-a strategy for overcoming drug resistance. J. Natl. Cancer Inst., 2001, 93(5), 347-357.
[http://dx.doi.org/10.1093/jnci/93.5.347] [PMID: 11238696]
[8]
Strelow, A.; Bernardo, K.; Adam-Klages, S.; Linke, T.; Sandhoff, K.; Krönke, M.; Adam, D. Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death. J. Exp. Med., 2000, 192(5), 601-612.
[http://dx.doi.org/10.1084/jem.192.5.601] [PMID: 10974027]
[9]
Hofmann, K.; Tomiuk, S.; Wolff, G.; Stoffel, W. Cloning and characterization of the mammalian brain-specific, Mg 2+ -dependent neutral sphingomyelinase. Proc. Natl. Acad. Sci. USA, 2000, 97(11), 5895-5900.
[http://dx.doi.org/10.1073/pnas.97.11.5895] [PMID: 10823942]
[10]
Hannun, Y.A.; Luberto, C. Ceramide in the eukaryotic stress response. Trends Cell Biol., 2000, 10(2), 73-80.
[http://dx.doi.org/10.1016/S0962-8924(99)01694-3] [PMID: 10652518]
[11]
Fox, T.E.; Finnegan, C.M.; Blumenthal, R.; Kester, M. The clinical potential of sphingolipid-based therapeutics. Cell. Mol. Life Sci., 2006, 63(9), 1017-1023.
[http://dx.doi.org/10.1007/s00018-005-5543-z] [PMID: 16568241]
[12]
Struckhoff, A.P.; Bittman, R.; Burow, M.E.; Clejan, S.; Elliott, S.; Hammond, T.; Tang, Y.; Beckman, B.S. Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J. Pharmacol. Exp. Ther., 2004, 309(2), 523-532.
[http://dx.doi.org/10.1124/jpet.103.062760] [PMID: 14742741]
[13]
Cai, Z.; Bettaieb, A.; Mahdani, N.E.; Legrès, L.G.; Stancou, R.; Masliah, J.; Chouaib, S. Alteration of the sphingomyelin/ceramide pathway is associated with resistance of human breast carcinoma MCF7 cells to tumor necrosis factor-alpha-mediated cytotoxicity. J. Biol. Chem., 1997, 272(11), 6918-6926.
[http://dx.doi.org/10.1074/jbc.272.11.6918] [PMID: 9054379]
[14]
Radin, N.S. Killing tumours by ceramide-induced apoptosis: A critique of available drugs. Biochem. J., 2003, 371(2), 243-256.
[http://dx.doi.org/10.1042/bj20021878] [PMID: 12558497]
[15]
Bansode, R.R.; Ahmedna, M.; Svoboda, K.R.; Losso, J.N. Coupling in vitro and in vivo paradigm reveals a dose dependent inhibition of angiogenesis followed by initiation of autophagy by C6-ceramide. Int. J. Biol. Sci., 2011, 7(5), 629-644.
[http://dx.doi.org/10.7150/ijbs.7.629] [PMID: 21647331]
[16]
Zhang, T.; Liu, J.; Zhang, Y.; Li, Y.; Lu, H.; Murata, N.; Yamakawa, T. Ceramide induces apoptosis in human lung adenocarcinoma A549 cells through mitogen-activated protein kinases. Acta Pharmacol. Sin., 2007, 28(3), 439-445.
[http://dx.doi.org/10.1111/j.1745-7254.2007.00505.x] [PMID: 17303009]
[17]
Kurinna, S.M.; Tsao, C.C.; Nica, A.F.; Jiffar, T.; Ruvolo, P.P. Ceramide promotes apoptosis in lung cancer-derived A549 cells by a mechanism involving c-Jun NH2-terminal kinase. Cancer Res., 2004, 64(21), 7852-7856.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1552] [PMID: 15520191]
[18]
Ravid, T.; Tsaba, A.; Gee, P.; Rasooly, R.; Medina, E.A.; Goldkorn, T. Ceramide accumulation precedes caspase-3 activation during apoptosis of A549 human lung adenocarcinoma cells. Am. J. Physiol. Lung Cell. Mol. Physiol., 2003, 284(6), L1082-L1092.
[http://dx.doi.org/10.1152/ajplung.00172.2002] [PMID: 12576296]
[19]
Kolesnick, R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J. Clin. Invest., 2002, 110(1), 3-8.
[http://dx.doi.org/10.1172/JCI0216127] [PMID: 12093880]
[20]
Vejselova, D.; Kutlu, H.M.; Kuş, G.; Kabadere, S.; Uyar, R. Cytotoxic and apoptotic effects of ceranib-2 offering potential for a new antineoplastic agent in the treatment of cancer cells. Turk. J. Biol., 2014, 38, 916-921.
[http://dx.doi.org/10.3906/biy-1405-36]
[21]
Draper, J.M.; Xia, Z.; Smith, R.A.; Zhuang, Y.; Wang, W.; Smith, C.D. Discovery and evaluation of inhibitors of human ceramidase. Mol. Cancer Ther., 2011, 10(11), 2052-2061.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0365] [PMID: 21885864]
[22]
Vethakanraj, H.S.; Babu, T.A.; Sudarsanan, G.B.; Duraisamy, P.K.; Ashok Kumar, S. Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines. Biochem. Biophys. Res. Commun., 2015, 464(3), 833-839.
[http://dx.doi.org/10.1016/j.bbrc.2015.07.047] [PMID: 26188095]
[23]
Beckham, T.H.; Lu, P.; Cheng, J.C.; Zhao, D.; Turner, L.S.; Zhang, X.; Hoffman, S.; Armeson, K.E.; Liu, A.; Marrison, T.; Hannun, Y.A.; Liu, X. Acid ceramidase-mediated production of sphingosine 1-phosphate promotes prostate cancer invasion through upregulation of cathepsin B. Int. J. Cancer, 2012, 131(9), 2034-2043.
[http://dx.doi.org/10.1002/ijc.27480] [PMID: 22322590]
[24]
Brizuela, L.; Martin, C.; Jeannot, P.; Ader, I.; Gstalder, C.; Andrieu, G.; Bocquet, M.; Laffosse, J.M.; Gomez-Brouchet, A.; Malavaud, B.; Sabbadini, R.A.; Cuvillier, O. Osteoblast-derived sphingosine 1-phosphate to induce proliferation and confer resistance to therapeutics to bone metastasis-derived prostate cancer cells. Mol. Oncol., 2014, 8(7), 1181-1195.
[http://dx.doi.org/10.1016/j.molonc.2014.04.001] [PMID: 24768038]
[25]
Proksch, D.; Klein, J.J.; Arenz, C. Potent inhibition of acid ceramidase by novel B-13 analogues. J. Lipids, 2011, 2011, 1-8.
[http://dx.doi.org/10.1155/2011/971618] [PMID: 21490813]
[26]
Osawa, Y.; Uchinami, H.; Bielawski, J.; Schwabe, R.F.; Hannun, Y.A.; Brenner, D.A. Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha. J. Biol. Chem., 2005, 280(30), 27879-27887.
[http://dx.doi.org/10.1074/jbc.M503002200] [PMID: 15946935]
[27]
Vejselova, D.; Kutlu, H.M.; Kuş, G. Examining impacts of ceranib-2 on the proliferation, morphology and ultrastructure of human breast cancer cells. Cytotechnology, 2016, 68(6), 2721-2728.
[http://dx.doi.org/10.1007/s10616-016-9997-7] [PMID: 27380965]
[28]
İzgördü, H.; Vejselova Sezer, C.; Çömlekçi, E.; Kutlu, H.M. Characteristics of apoptosis induction in human breast cancer cells treated with a ceramidase inhibitor. Cytotechnology, 2020, 72(6), 907-919.
[http://dx.doi.org/10.1007/s10616-020-00436-1] [PMID: 33270814]
[29]
Kutlu, H.M.; Vejselova, C.S.; Kus, G.; Comlekci, E.; Izgördü, H.A. 5-Fluorouracil derivative: Carmofur as a new potent agent for inhibition of human prostate and breast cancer cell lines. Iran. J. Sci. Technol. Trans. Sci., 2021.
[http://dx.doi.org/10.1007/s40995-021-01227-9]
[30]
Thorat, B.R.; Mali, S.N.; Wagh, R.R.; Yamgar, R.S. Synthesis, molecular docking, antioxidant, anti-tb, and potent MCF-7 anticancerstudies of novel aryl-carbohydrazideanalogues. Curr Comput Aided Drug Des, 2022.
[http://dx.doi.org/10.2174/1573409918666220610162158]
[31]
Mali, S.N.; Pandey, A. Synthesis of new hydrazones using a biodegradable catalyst, their biological evaluations and molecular modeling studies (Part-II). J. Comput. Biophys. Chem., 2022, 21(7), 857-882.
[http://dx.doi.org/10.1142/S2737416522500387]

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