Research Article
BibTex RIS Cite

Cytotoxic Effects of Resveratrol and Its Combinations with Ceramide Metabolism Inhibitors on FLT3 Positive Acute Myeloid Leukemia

Year 2020, , 1205 - 1216, 31.12.2020
https://doi.org/10.18185/erzifbed.764085

Abstract

Sphingolipids determine the cell fate by regulating cell proliferation and growth. Ceramide, growth inhibitory lipid, might be produced through de novo pathway or salvage pathway, which is converted to proliferation inducers sphingosine-1-phosphate (S1P) and glucosyl ceramide (GC) by sphingosine kinase (SK) and glucosyl ceramide synthase (GCS), respectively. It is aimed to investigate therapeutic potential of resveratrol on FLT3 overexpressing acute myeloid leukemia (AML) cells by pharmacological targeting of ceramide metabolism. The cytotoxic effects of resveratrol, SK inhibitor (SKI II), GCS inhibitor (PDMP) and the combinations of resveratrol with SK-1 inhibitor and GCS inhibitor on THP-1 and OCI-AML3 FLT3 overexpressing AML cells were investigated by MTT cell viability assay in a time- and concentration-dependent manner. Apoptotic effect of resveratrol was analyzed by annexin V/PI double staining using flow cytometry. Resveratrol decreased cell viability and induced apoptosis in both cell lines (p<0.05 considered significant). There were synergistic cytotoxic effects of resveratrol with co-administration of SK-1 inhibitor and GCS inhibitor at 48 h (p<0.05 considered significant). This preliminary data showed for the first time that resveratrol might inhibit the viability of FLT3 overexpressing AML cells through targeting ceramide metabolism and inducing apoptosis, which needs to be further clarified mechanistically.

Supporting Institution

Abdullah Gul University Scientific Reserach Projects Coordination Unit

Project Number

FAB-2016-66

References

  • Adan-Gokbulut, A., Kartal-Yandim, M., Iskender, G., Baran. Y. 2013.‘’ Novel agents targeting bioactive sphingolipids for the treatment of cancer’’, Curr Med Chem, 20, 108-22.
  • Adan, A., Baran, Y. 2016. ‘’Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling’’, Tumor Biology, 37(5), 5781-95.
  • Athar, M., Back, J.H., Kopelovich, L., Bickers, D.R., Kim, A.L. 2009.‘’Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms’’, Arch.Biochem. Biophys , 486:95:102.
  • Baran, Y., Salas, A., Senkal, C.E., Gunduz, U., Bielawski, J., Obeid, L.M., Ogretmen, B. 2007. ‘’ Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells’’, J Biol Chem, 282,10922-34.
  • Baribeau, S., Chaudhry, P., Parent, S., Asselin, É. 2014. ‘’ Resveratrol Inhibits Cisplatin-Induced Epithelial-To-Mesenchymal Transition in Ovarian Cancer Cell Lines’’, Plos One, 1:e86987.
  • Cakir, Z., Saydam, G., Sahin, F., Baran, Y. 2011. ‘’ The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells’’, Cancer Res Clin Oncol, 137(2):279-86.
  • Cai, H., Xie, X., Ji, L., Ruan, X., Zheng, Z. 2017. ‘’Sphingosine kinase 1: a novel independent prognosis biomarker in hepatocellular carcinoma’’, Oncol Lett, 13,2316-22.
  • Charytoniuk, T., Harasim-Symbor, E., Polak, A., Drygalski, K., Berk, K., Chabowski, A., Konstantynowicz-Nowicka, K. 2019.‘’ Influence of Resveratrol on Sphingolipid Metabolism in Hepatocellular Carcinoma Cells in Lipid Overload State’’, Anticancer Agents Med Chem, 19,121-129.
  • Chow, S.E., Kao, C.H., Liu, Y.T.A., Cheng, M.L., Yang, Y.W., Huang, Y.K., Hsu, C.C., Wang, J.S. 2014. ‘’Resveratrol induced ER expansion and ER caspase-mediated apoptosis in human nasopharyngeal carcinoma cells’’, Apoptosis, 19,527-541.
  • Daver, N., Schlenk, R.F., Russell, N.H., Levis, M.J. 2019.‘’Targeting FLT3 mutations in AML: review of current knowledge and evidence’’, Leukemia, 33, 299-312.
  • Dei Cas, M., Ghidoni, R. 2018. ‘’Cancer Prevention and Therapy with Polyphenols: Sphingolipid-Mediated Mechanisms’’, Nurients, 10(7):940.
  • Estey, E.H. 2019. ‘’Acute myeloid leukemia: 2019 update on risk-stratification and management’’, Am J Hematology, 93, 1267-1291.
  • Giussani, P., Tringali, C., Riboni, L., Viani, P., Venerando, B. 2014. ‘’Sphingolipids: key regulators of apoptosis and pivotal players in cancer drug resistance’’, Int J Mol Sci, 15, 4356-92.
  • Gokbulut, A.A., Apohan, E., Baran, Y. 2013. ‘’Resveratrol and Quercetin-Induced Apoptosis of Human 232B4 Chronic Lymphocytic Leukemia Cells by Activation of caspase-3 and Cell Cycle Arrest’’, Hematology, 3:144-50.
  • Grove, C.S., Vassiliou, G.S. 2014. ‘’Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer?’’, Dis Model Mech, 7, 941-51.
  • Kartal, M., Saydam, G., Sahin, F., Baran, Y. 2011.‘’Resveratrol triggers apoptosis through regulating ceramide metabolizing genes in human K562chronic myeloid leukemia cells’’, Nutr Cancer, 63:637-44.
  • Konig, H., Levis, M. 2015. ‘’Targeting FLT3 to treat leukemia’’, Expert Opin Ther Targets, 19, 37-54. Kroll, A., Cho, H.E., Kang, M.H. 2020. ‘’ Antineoplastic Agents Targeting Sphingolipid Pathways’’, Front. Oncol, 10, 833.
  • Kundu, J.K., Surh, Y.J. 2008. ‘’Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives’’, Cancer Lett, 269,243-61.
  • Lyman, S.D. 1995. ‘’Biology of FLT3 ligand and receptor’’, Int J Hematol, 62, 63–73.
  • Martelli, M.P., Sportoletti, P., Tiacci, E., Martelli, M.F., Falini, B. 2013. ‘’Mutational landscape of AML with normal cytogenetics: Biological and clinical implications’’, Blood Rev, 27,13-22.
  • Mizutani, N., Omori, Y., Kawamoto, Y., Sobue , S., Ichihara , M., Motoshi Suzuki , M., Kyogashima , M., Nakamura , M., Tamiya-Koizumi , K., Nozawa , Y., Murate, T. 2016. ‘’ Resveratrol-induced transcriptional up-regulation of ASMase (SMPD1) of human leukemia and cancer cells’’, Biochem Biophys Res Commun , 470:851-6.
  • Morad, S.A., Cabot, M.C. 2012. ‘’Ceramide-orchestrated signalling in cancer cells’’, Nat. Rev. Cancer, 13, 51-65.
  • Newton, J., Lima, S., Maceyka, M., Spiegel, S. 2015. ‘’ Revisiting the sphingolipid rheostat: Evolving concepts in cancer therapy’’, Exp Cell Res, 333:195-200.
  • Ogretmen, B., Hannun, Y.A. 2004. ‘’Biologicallyactive sphingolipids in cancer pathogenesis and treatment’’, Nat Rev Cancer, 8, 604-16.
  • Ozeki, K., Kiyoi, H., Hirose, Y., Iwai, M., Ninomiya, M., Kodera, Y., Miyawaki, S., Kuriyama, K., Shimazaki, C., Akiyama, H., Nishimura, M, Motoji, T., Shinagawa, K., Takeshita, A., Ueda, R., Ohno, R., Emi, N., Naoe, T. 2004. ‘’Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia’’, Blood,103,1901-8.
  • Rauf, A., Imran, M., Butt, M.S., Nadeem, M., Peters, D.G., Mubarak, M.S. 2018. ‘’ Resveratrol as an anti-cancer agent: A review’’, Crit Rev Food Sci Nutr, 58(9):1428-1447.
  • Robak T, Wierzbowska A. 2009. ‘’Current and emerging therapies for acute myeloid leukemia’’, Clin Ther, 2, 2349-70.
  • Scarlatti, F., Sala, G., Somenzi, G., Signorelli, P., Sacchi, N., Ghidoni, R. 2003.’’ Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling’’, FASEB J, 15:2339-41.
  • Shukla, Y., Singh, R. 2011. ‘’Resveratrol and cellular mechanisms of cancer prevention’’, Ann N Y Acad Sci, 1215,1-8.
  • Siedlecka-Kroplewska, K., Wozniak, M., Kmiec, Z. 2019. ‘’ The wine polyphenol resveratrol modulates autophagy and induces apoptosis in MOLT-4 and HL-60 human leukemia cells’’, J Physiol Pharmacol, 70.
  • Testa, U., Pelosi, E. 2013. ‘’The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias’’, Leuk Res Treatment, 2013, 1-14.
  • Tian, H., Yu, Z. 2015. ‘’Resveratrol induces apoptosis of leukemia cell line K562 by modulation of sphingosine kinase-1 pathway ‘’, Int J Clin Exp Pathol, 8(3):2755-62.
  • Truman, J.P., Garcia-Barros, M., Obeid, L.M., and Hannun, Y.A. 2014. ‘’Evolving concepts in cancer therapy through targeting sphingolipid metabolism’’, Biochim. Biophys. Acta, 1841, 1174-1188.
  • Wang, M., Yu, T., Zhu, C., Sun, H., Qui, Y., Zhu, X., Li, J. 2014. ‘’Resveratrol triggers protective autophagy through the ceramide/Akt/mTOR pathway in melanoma B16 cells’’, Nutr Cancer , 66:435-40.

Resveratrol ve Seramid Metabolizması Enzim İnhibitörleri İle Kombinasyonlarının FLT3 Pozitif Akut Miyeloid Lösemideki Sitotoksik Etkileri

Year 2020, , 1205 - 1216, 31.12.2020
https://doi.org/10.18185/erzifbed.764085

Abstract

Sfingolipidler hücre büyümesi ve çoğalmasını kontrol ederek hücrenin yaşam veya ölüm arasındaki kararını belirlemektedir. Büyümeyi baskılayıcı etkisi olan de novo yol izi veya salvage yol izi ile sentezlenen seramid sfingozin kinaz (SK) ve glukosil seramid sentaz (GSS) enzimleri tarafından sırasıyla hücre çoğalmasını destekleyici sfingozin-1-fosfat (S1F) ve glukozil seramide (GS) dönüştürülmektedir. Bu çalışmada, resveratrolün FLT3’yi aşırı ifade eden THP-1 ve OCI-AML3 hücreleri üzerindeki terapötik potansiyeli seramid metabolizmasının farmakolojik olarak hedeflenmesi ile araştırılmıştır. Resveratrol, SK inhibitörü (SKI II), GSS inhibitörü (PDMP) ve resveratrolün inhibitörler ile kombinasyonlarının THP-1 ve OCI-AML3 hücreleri üzerindeki sitotoksik etkileri konsantrasyona ve zamana bağlı olarak MTT hücre canlılık testi ile saptanmıştır. Resveratrolün apoptotik etkisi aneksin-V/PI ikili boyaması yapılarak akım sitometresi ile belirlenmiştir. Resveratrol her iki hücrede hücre canlılığını azaltmış ve apoptozu indüklemiştir (p<0.05 anlamlı olarak değerlendirilmiştir). Resveratolün SK ve GSS inhibitörleri ile kombinasyonlarının 48 saatlik muamele sonucu sinerjistik sitotoksik etki gösterdiği belirlenmiştir (p<0.05). Elde edilen bu sonuçlar, resveratrolün FLT3’yi aşırı ifade eden AML’de seramid metabolizmasını hedefleyerek etki gösterebileceğini literatürde ilk defa göstermiştir ve çalışma mekanistik olarak araştırılabilecektir.

Project Number

FAB-2016-66

References

  • Adan-Gokbulut, A., Kartal-Yandim, M., Iskender, G., Baran. Y. 2013.‘’ Novel agents targeting bioactive sphingolipids for the treatment of cancer’’, Curr Med Chem, 20, 108-22.
  • Adan, A., Baran, Y. 2016. ‘’Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling’’, Tumor Biology, 37(5), 5781-95.
  • Athar, M., Back, J.H., Kopelovich, L., Bickers, D.R., Kim, A.L. 2009.‘’Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms’’, Arch.Biochem. Biophys , 486:95:102.
  • Baran, Y., Salas, A., Senkal, C.E., Gunduz, U., Bielawski, J., Obeid, L.M., Ogretmen, B. 2007. ‘’ Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells’’, J Biol Chem, 282,10922-34.
  • Baribeau, S., Chaudhry, P., Parent, S., Asselin, É. 2014. ‘’ Resveratrol Inhibits Cisplatin-Induced Epithelial-To-Mesenchymal Transition in Ovarian Cancer Cell Lines’’, Plos One, 1:e86987.
  • Cakir, Z., Saydam, G., Sahin, F., Baran, Y. 2011. ‘’ The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells’’, Cancer Res Clin Oncol, 137(2):279-86.
  • Cai, H., Xie, X., Ji, L., Ruan, X., Zheng, Z. 2017. ‘’Sphingosine kinase 1: a novel independent prognosis biomarker in hepatocellular carcinoma’’, Oncol Lett, 13,2316-22.
  • Charytoniuk, T., Harasim-Symbor, E., Polak, A., Drygalski, K., Berk, K., Chabowski, A., Konstantynowicz-Nowicka, K. 2019.‘’ Influence of Resveratrol on Sphingolipid Metabolism in Hepatocellular Carcinoma Cells in Lipid Overload State’’, Anticancer Agents Med Chem, 19,121-129.
  • Chow, S.E., Kao, C.H., Liu, Y.T.A., Cheng, M.L., Yang, Y.W., Huang, Y.K., Hsu, C.C., Wang, J.S. 2014. ‘’Resveratrol induced ER expansion and ER caspase-mediated apoptosis in human nasopharyngeal carcinoma cells’’, Apoptosis, 19,527-541.
  • Daver, N., Schlenk, R.F., Russell, N.H., Levis, M.J. 2019.‘’Targeting FLT3 mutations in AML: review of current knowledge and evidence’’, Leukemia, 33, 299-312.
  • Dei Cas, M., Ghidoni, R. 2018. ‘’Cancer Prevention and Therapy with Polyphenols: Sphingolipid-Mediated Mechanisms’’, Nurients, 10(7):940.
  • Estey, E.H. 2019. ‘’Acute myeloid leukemia: 2019 update on risk-stratification and management’’, Am J Hematology, 93, 1267-1291.
  • Giussani, P., Tringali, C., Riboni, L., Viani, P., Venerando, B. 2014. ‘’Sphingolipids: key regulators of apoptosis and pivotal players in cancer drug resistance’’, Int J Mol Sci, 15, 4356-92.
  • Gokbulut, A.A., Apohan, E., Baran, Y. 2013. ‘’Resveratrol and Quercetin-Induced Apoptosis of Human 232B4 Chronic Lymphocytic Leukemia Cells by Activation of caspase-3 and Cell Cycle Arrest’’, Hematology, 3:144-50.
  • Grove, C.S., Vassiliou, G.S. 2014. ‘’Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer?’’, Dis Model Mech, 7, 941-51.
  • Kartal, M., Saydam, G., Sahin, F., Baran, Y. 2011.‘’Resveratrol triggers apoptosis through regulating ceramide metabolizing genes in human K562chronic myeloid leukemia cells’’, Nutr Cancer, 63:637-44.
  • Konig, H., Levis, M. 2015. ‘’Targeting FLT3 to treat leukemia’’, Expert Opin Ther Targets, 19, 37-54. Kroll, A., Cho, H.E., Kang, M.H. 2020. ‘’ Antineoplastic Agents Targeting Sphingolipid Pathways’’, Front. Oncol, 10, 833.
  • Kundu, J.K., Surh, Y.J. 2008. ‘’Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives’’, Cancer Lett, 269,243-61.
  • Lyman, S.D. 1995. ‘’Biology of FLT3 ligand and receptor’’, Int J Hematol, 62, 63–73.
  • Martelli, M.P., Sportoletti, P., Tiacci, E., Martelli, M.F., Falini, B. 2013. ‘’Mutational landscape of AML with normal cytogenetics: Biological and clinical implications’’, Blood Rev, 27,13-22.
  • Mizutani, N., Omori, Y., Kawamoto, Y., Sobue , S., Ichihara , M., Motoshi Suzuki , M., Kyogashima , M., Nakamura , M., Tamiya-Koizumi , K., Nozawa , Y., Murate, T. 2016. ‘’ Resveratrol-induced transcriptional up-regulation of ASMase (SMPD1) of human leukemia and cancer cells’’, Biochem Biophys Res Commun , 470:851-6.
  • Morad, S.A., Cabot, M.C. 2012. ‘’Ceramide-orchestrated signalling in cancer cells’’, Nat. Rev. Cancer, 13, 51-65.
  • Newton, J., Lima, S., Maceyka, M., Spiegel, S. 2015. ‘’ Revisiting the sphingolipid rheostat: Evolving concepts in cancer therapy’’, Exp Cell Res, 333:195-200.
  • Ogretmen, B., Hannun, Y.A. 2004. ‘’Biologicallyactive sphingolipids in cancer pathogenesis and treatment’’, Nat Rev Cancer, 8, 604-16.
  • Ozeki, K., Kiyoi, H., Hirose, Y., Iwai, M., Ninomiya, M., Kodera, Y., Miyawaki, S., Kuriyama, K., Shimazaki, C., Akiyama, H., Nishimura, M, Motoji, T., Shinagawa, K., Takeshita, A., Ueda, R., Ohno, R., Emi, N., Naoe, T. 2004. ‘’Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia’’, Blood,103,1901-8.
  • Rauf, A., Imran, M., Butt, M.S., Nadeem, M., Peters, D.G., Mubarak, M.S. 2018. ‘’ Resveratrol as an anti-cancer agent: A review’’, Crit Rev Food Sci Nutr, 58(9):1428-1447.
  • Robak T, Wierzbowska A. 2009. ‘’Current and emerging therapies for acute myeloid leukemia’’, Clin Ther, 2, 2349-70.
  • Scarlatti, F., Sala, G., Somenzi, G., Signorelli, P., Sacchi, N., Ghidoni, R. 2003.’’ Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling’’, FASEB J, 15:2339-41.
  • Shukla, Y., Singh, R. 2011. ‘’Resveratrol and cellular mechanisms of cancer prevention’’, Ann N Y Acad Sci, 1215,1-8.
  • Siedlecka-Kroplewska, K., Wozniak, M., Kmiec, Z. 2019. ‘’ The wine polyphenol resveratrol modulates autophagy and induces apoptosis in MOLT-4 and HL-60 human leukemia cells’’, J Physiol Pharmacol, 70.
  • Testa, U., Pelosi, E. 2013. ‘’The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias’’, Leuk Res Treatment, 2013, 1-14.
  • Tian, H., Yu, Z. 2015. ‘’Resveratrol induces apoptosis of leukemia cell line K562 by modulation of sphingosine kinase-1 pathway ‘’, Int J Clin Exp Pathol, 8(3):2755-62.
  • Truman, J.P., Garcia-Barros, M., Obeid, L.M., and Hannun, Y.A. 2014. ‘’Evolving concepts in cancer therapy through targeting sphingolipid metabolism’’, Biochim. Biophys. Acta, 1841, 1174-1188.
  • Wang, M., Yu, T., Zhu, C., Sun, H., Qui, Y., Zhu, X., Li, J. 2014. ‘’Resveratrol triggers protective autophagy through the ceramide/Akt/mTOR pathway in melanoma B16 cells’’, Nutr Cancer , 66:435-40.
There are 34 citations in total.

Details

Primary Language English
Subjects Engineering
Journal Section Makaleler
Authors

Nur Şebnem Ersöz This is me 0000-0003-3343-9936

Aysun Adan 0000-0002-3747-8580

Project Number FAB-2016-66
Publication Date December 31, 2020
Published in Issue Year 2020

Cite

APA Ersöz, N. Ş., & Adan, A. (2020). Cytotoxic Effects of Resveratrol and Its Combinations with Ceramide Metabolism Inhibitors on FLT3 Positive Acute Myeloid Leukemia. Erzincan University Journal of Science and Technology, 13(3), 1205-1216. https://doi.org/10.18185/erzifbed.764085