Investigation of the antiproliferative effect of ceramide and sphingomyelin on various cell lines
Year 2025,
Volume: 34 Issue: 2, 46 - 52
Seyma Buse Saglamer
,
Aysun Keskin
,
Necmettin Yılmaz
,
Ercan Cacan
Abstract
Sphingolipids participate in the structure of the cell membrane and have bioactive roles in many cellular events, including cell proliferation, differentiation, and programmed cell death. Changes in sphingolipid metabolism contribute to the formation and progression of the cancer phenotype in different cancer types and multi-drug resistance. In this study, we aimed to examine the antiproliferative effects of ceramide and sphingomyelin on different cancer cell lines. The results showed that ceramide and sphingomyelin act similarly and have antiproliferative effects on three different cancer cell lines and a normal cell line in a dose-dependent manner. In contrast, this effect decreases when low concentrations are applied. In DMSO solvent, ceramide was most effective in C6 cells (IC50 = 32.7 μM) and least in CCD-18Co (IC50 = 56.91 μM). In ethanol, it showed highest sensitivity in CCD-18Co (IC50 = 0.33 μM). Sphingomyelin in DMSO had IC50 values of 0.25 μM in C6 and HT29 and 0.45 μM in CCD-18Co. In ethanol, it was more effective in cancer cells (IC50 = 0.25–0.28 μM) but less cytotoxic in CCD-18Co. In conclusion, these two molecules have antiproliferative activities in a dose-dependent manner, however, further molecular investigations are needed to understand the mechanism of actions.
Supporting Institution
Tokat Gaziosmanpaşa University
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https://doi.org/10.1016/S0304-3835(03)00050-8
Year 2025,
Volume: 34 Issue: 2, 46 - 52
Seyma Buse Saglamer
,
Aysun Keskin
,
Necmettin Yılmaz
,
Ercan Cacan
References
-
Airola, M. V, & Hannun, Y. A. (2013). Sphingolipid metabolism and neutral sphingomyelinases. Sphingolipids: Basic Science and Drug Development, 57–76. https://doi.org/10.1007/978-3-7091-1368-4_3
-
Al-Janabi, A. S., Alheety, M. A., Osama'a, A. Y., Shaaban, S., Kibar, B., & Cacan, E. (2020). Anti-cancer and anti-fungal evaluation of novel palladium (II) 1-phenyl-1H-tetrazole-5-thiol complexes. Inorganic Chemistry Communications, 121, 108193. https://doi.org/10.1016/j.inoche.2020.108193
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Alizadeh, J., da Silva Rosa, S. C., Weng, X., Jacobs, J., Lorzadeh, S., Ravandi, A., Vitorino, R., Pecic, S., Zivkovic, A., Stark, H., Shojaei, S., & Ghavami, S. (2023). Ceramides and ceramide synthases in cancer: Focus on apoptosis and autophagy. European Journal of Cell Biology, 102 (3), 151337. https://doi.org/10.1016/j.ejcb.2023.151337
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Bansode, R. R., Ahmedna, M., Svoboda, K. R., & Losso, J. N. (2011). Coupling in vitro and in vivo paradigm reveals a dose dependent inhibition of angiogenesis followed by initiation of autophagy by C6-ceramide. International Journal of Biological Sciences, 7(5), 629. https://doi.org/10.7150/ijbs.7.629
-
Berkel, C., Kucuk, B., Usta, M., Yilmaz, E., & Cacan, E. (2020). The Effect of Olaparib and Bortezomib Combination Treatment on Ovarian Cancer Cell Lines. European Journal of Biology, 79(2), 115–123.
https://doi.org/10.26650/EurJBiol.2020.0035
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Bienias, K., Fiedorowicz, A., Sadowska, A., Prokopiuk, S., & Car, H. (2016). Regulation of sphingomyelin metabolism. Pharmacological Reports, 68(3), 570–581.
https://doi.org/10.1016/j.pharep.2015.12.008
-
Butler, L. M., Perone, Y., Dehairs, J., Lupien, L. E., de Laat, V., Talebi, A., Loda, M., Kinlaw, W. B., & Swinnen, J. V. (2020). Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention. Advanced Drug Delivery Reviews, 159, 245–293. https://doi.org/10.1016/j.addr.2020.07.013
-
Cacan, E., & Ozmen, Z. C. (2020). Regulation of Fas in response to bortezomib and epirubicin in colorectal cancer cells. Journal of Chemotherapy, 32(4), 193–201.
https://doi.org/10.1080/1120009X.2020.1740389
-
Chang, Y., Fong, Y., Tsai, E.-M., Chang, Y.-G., Chou, H., Wu, C.-Y., Teng, Y.-N., Liu, T.-C., Yuan, S.-S., & Chiu, C.-C. (2018). Exogenous C8-Ceramide Induces Apoptosis by Overproduction of ROS and the Switch of Superoxide Dismutases SOD1 to SOD2 in Human Lung Cancer Cells. International Journal of Molecular Sciences, 19(10), 3010. https://doi.org/10.3390/ijms19103010
-
Ding, S., Li, G., Fu, T., Zhang, T., Lu, X., Li, N., & Geng, Q. (2024). Ceramides and mitochondrial homeostasis. Cellular Signalling, 111099. https://doi.org/10.1016/j.cellsig.2024.111099
-
Falluel-Morel, A., Aubert, N., Vaudry, D., Desfeux, A., Allais, A., Burel, D., Basille, M., Vaudry, H., Laudenbach, V., & Gonzalez, B. J. (2008). Interactions of PACAP and ceramides in the control of granule cell apoptosis during cerebellar development. Journal of Molecular Neuroscience, 36(1), 8–15. https://doi.org/10.1007/s12031-008-9111-5
-
Fillet, M., Bentires-Alj, M., Deregowski, V., Greimers, R., Gielen, J., Piette, J., Bours, V., & Merville, M.-P. (2003). Mechanisms involved in exogenous C2- and C6-ceramide-induced cancer cell toxicity. Biochemical Pharmacology, 65(10), 1633–1642. https://doi.org/10.1016/S0006-2952(03)00125-4
-
Futerman, A. H., & Hannun, Y. A. (2004). The complex life of simple sphingolipids. EMBO Reports, 5(8), 777–782. https://doi.org/10.1038/sj.embor.7400208
-
Gencer, S. (2019). Impact of the Ceramide Metabolism on Primary Cilia Length and Tumor Metastasis in HNSCC Cells. Bilecik Şeyh Edebali Üniversitesi Fen Bilimleri Dergisi, 6, 213-221.
https://doi.org/10.35193/bseufbd.601582
-
Hadjira, S., Mansour, A., Berkel, C., Seghiri, R., Menad, A., Benayache, F., Benayache, S., Cacan, E., & Ameddah, S. (2021). Antioxidant, Anti-Inflammatory and Cytotoxic Properties of Centaurea africana Lamk var. [Bonnet] M. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 20(1), 89–100. https://doi.org/10.2174/1871523019666200609140532
-
Huang, W.-C., Chen, C.-L., Lin, Y.-S., & Lin, C.-F. (2011). Apoptotic Sphingolipid Ceramide in Cancer Therapy. Journal of Lipids, 2011, 565316. https://doi.org/10.1155/2011/565316
-
Ji, C., Yang, B., Yang, Y. L., He, S. H., Miao, D. S., He, L., & Bi, Z. G. (2010). Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition. Oncogene, 29(50), 6557–6568. https://doi.org/10.1038/onc.2010.379
-
Kolesnick, R. (2002). The therapeutic potential of modulating the ceramide/sphingomyelin pathway. The Journal of Clinical Investigation, 110(1), 3-8. https://doi:10.1172/JCI200216127
-
Li, F., & Zhang, N. (2015). Ceramide: Therapeutic Potential in Combination Therapy for Cancer Treatment. Current Drug Metabolism, 17(1), 37–51. https://doi.org/10.2174/1389200216666151103120338
-
Merz, N., Hartel, J. C., & Grösch, S. (2024). How ceramides affect the development of colon cancer: from normal colon to carcinoma. Pflügers Archiv-European Journal of Physiology, 1-14. https://doi.org/10.1007/s00424-024-02960-x
-
Mesicek, J., Lee, H., Feldman, T., Jiang, X., Skobeleva, A., Berdyshev, E. V, Haimovitz-Friedman, A., Fuks, Z., & Kolesnick, R. (2010). Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells. Cellular Signalling, 22(9), 1300–1307. https://doi.org/10.1016/j.cellsig.2010.04.006
-
Morad, S. A. F., & Cabot, M. C. (2013). Ceramide-orchestrated signalling in cancer cells. Nature Reviews Cancer, 13(1), 51–65. https://doi.org/10.1038/nrc3398
-
Martin-Perez, M., Urdiroz-Urricelqui, U., Bigas, C., & Benitah, S. A. (2022). The role of lipids in cancer progression and metastasis. Cell Metabolism, 34(11), 1675-1699. https://doi.org/10.1016/j.cmet.2022.09.023
-
Nguyen, T. V, Alfarsi, A., Nguyen, H. T., Davidson, G., Lloyd, N. D. R., & Kumar, A. (2025). Metabolic Disruptions Induced by Low Concentrations of DMSO in RTgill-W1 Fish Cells: The Importance of Solvent Controls in in vitro Studies. Aquatic Toxicology, 107354.
-
Ogretmen, B. (2018). Sphingolipid metabolism in cancer signalling and therapy. Nature Reviews Cancer, 18(1), 33–50. https://doi.org/10.1038/nrc.2017.96
-
Patwardhan, G. A., & Liu, Y.-Y. (2011). Sphingolipids and expression regulation of genes in cancer. Progress in Lipid Research, 50(1), 104–114. https://doi.org/10.1016/j.plipres.2010.10.003
-
Selzner, M., Bielawska, A., Morse, M. A., Rüdiger, H. A., Sindram, D., Hannun, Y. A., & Clavien, P.-A. (2001). Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Research, 61(3), 1233–1240.
-
Shen, X., Feng, R., Zhou, R., Zhang, Z., Liu, K., & Wang, S. (2025). Ceramide as a Promising Tool for Diagnosis and Treatment of Clinical Diseases: A Review of Recent Advances. Metabolites, 15(3), 195.
Skehan, P., Storeng, R., Scudiero, D., Monks, A., McMahon, J., Vistica, D., Warren, J. T., Bokesch, H., Kenney, S., & Boyd, M. R. (1990). New colorimetric cytotoxicity assay for anticancer-drug screening. JNCI: Journal of the National Cancer Institute, 82(13), 1107–1112. https://doi.org/10.1093/jnci/82.13.1107
-
Song, L., Han, R., Yin, H., Li, J., Zhang, Y., Wang, J., Yang, Z., Bai, J., & Guo, M. (2022). Sphingolipid metabolism plays a key role in diabetic peripheral neuropathy. Metabolomics, 18(6), 1–10. https://doi.org/10.1007/s11306-022-01879-7
-
Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249. https://doi.org/10.3322/caac.21660
-
Toman, R. E., Movsesyan, V., Murthy, S. K., Milstien, S., Spiegel, S., & Faden, A. I. (2002). Ceramide‐induced cell death in primary neuronal cultures: upregulation of ceramide levels during neuronal apoptosis. Journal of Neuroscience Research, 68(3), 323–330.
-
Xie, Y., Zeng, Q., Chen, Z., Song, J., Wang, F., Liu, D., Sun, X., Zhang, Y., & Huang, Q. (2025). Dysregulation of sphingolipid metabolism contributes to the pathogenesis of chronic myeloid leukemia. Cell Death & Disease, 16(1), 282.
-
Wang, Z., Li, W., Jiang, Y., Park, J., Gonzalez, K. M., Wu, X., ... & Lu, J. (2024). Cholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery. Nature Communications, 15(1), 2073. https://doi.org/10.1038/s41467-024-46331-7
-
Yan, K., Zhang, W., Song, H., & Xu, X. (2024). Sphingolipid metabolism and regulated cell death in malignant melanoma. Apoptosis, 1-19. https://doi.org/10.1007/s10495-024-02002-y
-
Zhakupova, A., Zeinolla, A., Kokabi, K., Sergazy, S., & Aljofan, M. (2025). Drug Resistance: The Role of Sphingolipid Metabolism. International Journal of Molecular Sciences, 26(8), 3716.
-
Zhou, S., Sun, L., Mao, F., & Chen, J. (2024). Sphingolipids in prostate cancer prognosis: integrating single-cell and bulk sequencing. Aging (Albany NY), 16(9), 8031. https://doi.org/10.18632/aging.205803
-
Zhu, X.-F., Liu, Z.-C., Xie, B.-F., Feng, G.-K., & Zeng, Y.-X. (2003). Ceramide induces cell cycle arrest and upregulates p27kip in nasopharyngeal carcinoma cells. Cancer Letters, 193(2), 149–154.
https://doi.org/10.1016/S0304-3835(03)00050-8