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


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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.

Sobre autores

filiz Alanyalı

Department of Biology, Faculty of Science, Eskisehir Technical University

Autor responsável pela correspondência
Email: info@benthamscience.net

Osman Algı

Department of Biology, Faculty of Science,, Eskisehir Technical University

Email: info@benthamscience.net

Bibliografia

  1. Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70. doi: 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. doi: 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. doi: 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. doi: 10.1038/nrc1411 PMID: 15286740
  5. Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat. Rev. Cancer, 2018, 18(1), 33-50. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1142/S2737416522500387

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