Research Article
Oksipösedanin kaynaklı antikanser aktivitenin in siliko ve in vitro değerlendirilmesi: Mitotoksisite?
Abstract
Amaç: Çalışmanın amacı, farklı ortamlarda Oksipösedanin (OKS) aracılı antikanser aktivitedeki değişiklikleri değerlendirmektir. İkinci amaç, OKS’inin elektron transfer zincirine (ETZ) karşı afinitesini öngörmektir.
Gereç ve Yöntem: MTT ve LDH sızma deneyleri OKS ile gerçekleştirilmiştir. Ayrıca, OKS’inin ETZ komplekslerine karşı afinitesini öngörmek için moleküler kenetlenme çalışmaları uygulanmıştır.
Bulgular: Glukoz içeren ortamda 250 µM OKS canlılığı azaltmıştır. Galaktoz içeren ortamda ≥50 µM OKS hücre canlılığını azalmıştır. Galaktoz içeren ortamda ≥50 µM OKS membran parçalanmasını artırmıştır. Moleküler kenetlenme çalışmaları, OKS'inin Kompleks I ve IV'ün inhibisyon bölgelerine bağlanma kapasitesine sahip olabileceğini göstermektedir.
Sonuç: Galaktoz içeren ortam, OKS aracılı sitotoksisiteyi artırmıştır. Ön sonuçlar, antikanser aktivitede mitotoksisitenin yer alabileceğini göstermektedir. Ayrıca OKS, Kompleks I ve IV'ün seçici inhibisyonu nedeni ile ETZ disfonksiyonuna neden olabilmektedir.
Ethical Statement
There was no data obtained from animal or human experiments for this article.
Supporting Institution
Çalışma, herhangi bir kurum tarafından desteklenmemiştir.
Project Number
Çalışma, herhangi bir proje tarafından desteklenmemiştir.
Thanks
All of the authors gratefully thank Prof. Ayşe NALBANTSOY (Bioengineering Department, Ege University) for the laboratory facilities.
References
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- Wong SC, Kamarudin MNA, Naidu R. Anticancer Mechanism of Curcumin on Human Glioblastoma. Nutrients. 2021;13(3):950. doi:10.3390/nu13030950
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- Pfeffer CM, Singh ATK. Apoptosis: A Target for Anticancer Therapy. International Journal of Molecular Sciences. 2018;19(2):448. doi:10.3390/ijms19020448
- Liu Y, Shi Y. Mitochondria as a target in cancer treatment. MedComm. 2020;1(2):129-139. doi:10.1002/mco2.16
- Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nature Reviews. Drug Discovery. 2010;9(6):447-464. doi:10.1038/nrd3137
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- Pereira CV, Oliveira PJ, Will Y, Nadanaciva S. Mitochondrial bioenergetics and drug-induced toxicity in a panel of mouse embryonic fibroblasts with mitochondrial DNA single nucleotide polymorphisms. Toxicology and Applied Pharmacology. 2012;264(2):167-181. doi:10.1016/j.taap.2012.07.030
- Ong MM, Latchoumycandane C, Boelsterli UA. Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicological Sciences. 2007;97(1):205-213. doi:10.1093/toxsci/kfl180
- Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H. The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology. 2011;251(3):226-233. doi:10.1016/j.taap.2011.01.004
- Diaz-Ruiz R, Rigoulet M, Devin A. The Warburg and Crabtree effects: On the origin of cancer cell energy metabolism and of yeast glucose repression. Biochimica et Biophysica Acta. 2011;1807(6):568-576. doi:10.1016/j.bbabio.2010.08.010
- Pascale RM, Calvisi DF, Simile MM, Feo CF, Feo F. The Warburg Effect 97 Years after Its Discovery. Cancers (Basel). 2020;12(10):2819. doi:10.3390/cancers12102819
- Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicological Sciences. 2007;97(2):539-547. doi:10.1093/toxsci/kfm052
- Swiss R, Will Y. Assessment of mitochondrial toxicity in HepG2 cells cultured in high-glucose- or galactose-containing media. Current Protocols in Toxicology. 2011;49(1):2-20. doi:10.1002/0471140856.tx0220s49
- Will Y, Dykens J. Mitochondrial toxicity assessment in industry-a decade of technology development and insight. Expert Opinion on Drug Metabolism Toxicology. 2014;10(8):1061-1067. doi:10.1517/17425255.2014.939628
- Dott W, Mistry P, Wright J, Cain K, Herbert KE. Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity. Redox Biology. 2014;2:224-233. doi:10.1016/j.redox.2013.12.028
- Tavakoli S, Delnavazi MR, Hadjiaghaee R, et al. Bioactive coumarins from the roots and fruits of Ferulago trifida Boiss., an endemic species to Iran. Natural Product Research. 2018;32(22):2724-2728. doi:10.1080/14786419.2017.1375915
- Kim YK, Kim YS, Ryu SY. Antiproliferative effect of furanocoumarins from the root of Angelica dahurica on cultured human tumor cell lines. Phytotherapy Research. 2007;21(3):288-290. doi:10.1002/ptr.2043
- Mottaghipisheh J, Nové M, Spengler G, Kúsz N, Hohmann J, Csupor D. Antiproliferative and cytotoxic activities of furocoumarins of Ducrosia anethifolia. Pharmaceutical Biology. 2018;56(1):658-664. doi:10.1080/13880209.2018.1548625
- Albayrak G, Demir S, Kose FA, Baykan S. New coumarin glycosides from endemic Prangos heyniae H. Duman & M.F. Watson. Natural Product Research. 2023;37(2):227-239. doi:10.1080/14786419.2021.1961138
- Kuzu B, Ergüç A, Karakuş F, Arzuk E. Design, synthesis, and antiproliferative activities of novel thiazolyl-pyrazole hybrid derivatives. Medicinal Chemistry Research. 2023;32:1690-1700. doi:10.1007/s00044-023-03090-2
- Ergüç A, Karakuş F, Arzuk E, Mutlu N, Orhan H. Role of Oxidative Stress and Reactive Metabolites in Cytotoxicity & Mitotoxicity of Clozapine, Diclofenac and Nifedipine in CHO-K1 Cells In Vitro. Endocrine, Metabolic & Immune Disorders Drug Targets. 2023;(in press). doi: 10.2174/1871530323666230419084613
- Guo R, Zong S, Wu M, Gu J, Yang M. Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2. Cell. 2017;170(6):1247-1257. doi:10.1016/j.cell.2017.07.050
- Du Z, Zhou X, Lai Y, et al. Structure of the human respiratory complex II. Proceedings of the National Academy of Sciences of the United States of America. 2023;120(18). doi:10.1073/pnas.2216713120
- Zong S, Wu M, Gu J, Liu T, Guo R, Yang M. Structure of the intact 14-subunit human cytochrome c oxidase. Cell Research. 2018;28(10):1026-1034. doi:10.1038/s41422-018-0071-1
- Heinz S, Freyberger A, Lawrenz B, Schladt L, Schmuck G, Ellinger-Ziegelbauer H. Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation. Scientific Reports. 2017;7:45465. doi:10.1038/srep45465
- Patra S, Pradhan B, Nayak R, et al. Apoptosis and autophagy modulating dietary phytochemicals in cancer therapeutics: Current evidences and future perspectives. Phytotherapy Research. 2021;35(8):4194-4214. doi:10.1002/ptr.7082
- Sitarek P, Synowiec E, Kowalczyk T, et al. Anticancer Properties of Plectranthus ornatus-Derived Phytochemicals Inducing Apoptosis via Mitochondrial Pathway. International Journal of Molecular Sciences. 2022;23(19):11653. doi:10.3390/ijms231911653
- Xiao J, Wang J, Yuan L, Hao L, Wang D. Study on the mechanism and intervention strategy of sunitinib induced nephrotoxicity. European Journal of Pharmacology. 2019;864:172709. doi:10.1016/j.ejphar.2019.172709
- Jalilian F, Moieni-Arya M, Hosseinzadeh L, Shokoohinia Y. Oxypeucedanin and isoimperatorin extracted from Prangos ferulacea (L.) Lindl protect PC12 pheochromocytoma cells from oxidative stress and apoptosis induced by doxorubicin. Research in Pharmaceutical Sciences. 2021;17(1):12-21. doi:10.4103/1735-5362.329922
- Jalilian F, Moieni-Arya M, Hosseinzadeh L, Shokoohinia Y. Oxypeucedanin and isoimperatorin extracted from Prangos ferulacea (L.) Lindl protect PC12 pheochromocytoma cells from oxidative stress and apoptosis induced by doxorubicin. Research in Pharmaceutical Sciences. 2021;17(1):12-21. doi:10.4103/1735-5362.329922
- Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell. 2015;162(3):540-551. doi:10.1016/j.cell.2015.07.016
- Li Y, Park JS, Deng JH, Bai Y. Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complex. Journal of Bioenergetics and Biomembranes. 2006;38(5-6):283-291. doi:10.1007/s10863-006-9052-z
Year 2023,
Volume: 9 Issue: 3, 153 - 161, 31.12.2023
Abstract
Aim: This study aims to evaluate the alterations in Oxypeucedanin (OXY)-mediated anticancer activity in different media. Second aim is to predict the affinity of OXY to electron transfer chain (ETC) complexes.
Materials and Methods: MTT and LDH leakage assays were performed with OXY. Molecular docking studies were also conducted to predict the affinity of OXY to ETC complexes.
Results: 250 µM OXY reduced viability in glucose media. ≥50 µM OXY decreased viability in galactose media. ≥50 µM OXY increased membrane disruption in galactose media. Molecular docking studies also showed that OXY might possess the capacity to bind to the inhibition sites of Complex I and IV.
Conclusion: Galactose-conditioned media exacerbated the OXY-mediated cytotoxicity. Preliminary results suggested that mitotoxicity might take part in anticancer activity. Furthermore, OXY might cause ETC dysfunctions due to selective inhibition of Complex I and IV.
Ethical Statement
There was no data obtained from animal or human experiments for this article.
Supporting Institution
All of the authors declared that this article has received no financial support.
Project Number
Çalışma, herhangi bir proje tarafından desteklenmemiştir.
Thanks
All of the authors gratefully thank Prof. Ayşe NALBANTSOY (Bioengineering Department, Ege University) for the laboratory facilities.
References
- González-Vallinas M, González-Castejón M, Rodríguez-Casado A, Ramírez de Molina A. Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising perspectives. Nutrition Reviews. 2013;71(9):585-599. doi: 10.1111/nure.12051
- Wong SC, Kamarudin MNA, Naidu R. Anticancer Mechanism of Curcumin on Human Glioblastoma. Nutrients. 2021;13(3):950. doi:10.3390/nu13030950
- Mottaghipisheh J, Kiss T, Tóth B, Csupor D. The Prangos genus: a comprehensive review on traditional use, phytochemistry, and pharmacological activities. Phytochemistry Reviews. 2020;19(6):1449-1470. doi: 10.1007/s11101-020-09688-3
- Mottaghipisheh J. Oxypeucedanin: Chemotaxonomy, Isolation, and Bioactivities. Plants (Basel). 2021;10(8):1577. doi:10.3390/plants10081577
- Oh H, Lee HS, Kim T, et al. Furocoumarins from Angelica dahurica with hepatoprotective activity on tacrine-induced cytotoxicity in HepG2 cells. Planta Medica. 2002;68(5):463-464. doi:10.1055/s-2002-32075
- Park SH, Hong JY, Park HJ, Lee SK. The Antiproliferative Activity of Oxypeucedanin via Induction of G2/M Phase Cell Cycle Arrest and p53-Dependent MDM2/p21 Expression in Human Hepatoma Cells. Molecules. 2020;25(3):501. doi:10.3390/molecules25030501
- Pfeffer CM, Singh ATK. Apoptosis: A Target for Anticancer Therapy. International Journal of Molecular Sciences. 2018;19(2):448. doi:10.3390/ijms19020448
- Liu Y, Shi Y. Mitochondria as a target in cancer treatment. MedComm. 2020;1(2):129-139. doi:10.1002/mco2.16
- Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nature Reviews. Drug Discovery. 2010;9(6):447-464. doi:10.1038/nrd3137
- Badrinath N, Yoo SY. Mitochondria in cancer: in the aspects of tumorigenesis and targeted therapy. Carcinogenesis. 2018;39(12):1419-1430. doi:10.1093/carcin/bgy148
- Pereira CV, Oliveira PJ, Will Y, Nadanaciva S. Mitochondrial bioenergetics and drug-induced toxicity in a panel of mouse embryonic fibroblasts with mitochondrial DNA single nucleotide polymorphisms. Toxicology and Applied Pharmacology. 2012;264(2):167-181. doi:10.1016/j.taap.2012.07.030
- Ong MM, Latchoumycandane C, Boelsterli UA. Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicological Sciences. 2007;97(1):205-213. doi:10.1093/toxsci/kfl180
- Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H. The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology. 2011;251(3):226-233. doi:10.1016/j.taap.2011.01.004
- Diaz-Ruiz R, Rigoulet M, Devin A. The Warburg and Crabtree effects: On the origin of cancer cell energy metabolism and of yeast glucose repression. Biochimica et Biophysica Acta. 2011;1807(6):568-576. doi:10.1016/j.bbabio.2010.08.010
- Pascale RM, Calvisi DF, Simile MM, Feo CF, Feo F. The Warburg Effect 97 Years after Its Discovery. Cancers (Basel). 2020;12(10):2819. doi:10.3390/cancers12102819
- Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicological Sciences. 2007;97(2):539-547. doi:10.1093/toxsci/kfm052
- Swiss R, Will Y. Assessment of mitochondrial toxicity in HepG2 cells cultured in high-glucose- or galactose-containing media. Current Protocols in Toxicology. 2011;49(1):2-20. doi:10.1002/0471140856.tx0220s49
- Will Y, Dykens J. Mitochondrial toxicity assessment in industry-a decade of technology development and insight. Expert Opinion on Drug Metabolism Toxicology. 2014;10(8):1061-1067. doi:10.1517/17425255.2014.939628
- Dott W, Mistry P, Wright J, Cain K, Herbert KE. Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity. Redox Biology. 2014;2:224-233. doi:10.1016/j.redox.2013.12.028
- Tavakoli S, Delnavazi MR, Hadjiaghaee R, et al. Bioactive coumarins from the roots and fruits of Ferulago trifida Boiss., an endemic species to Iran. Natural Product Research. 2018;32(22):2724-2728. doi:10.1080/14786419.2017.1375915
- Kim YK, Kim YS, Ryu SY. Antiproliferative effect of furanocoumarins from the root of Angelica dahurica on cultured human tumor cell lines. Phytotherapy Research. 2007;21(3):288-290. doi:10.1002/ptr.2043
- Mottaghipisheh J, Nové M, Spengler G, Kúsz N, Hohmann J, Csupor D. Antiproliferative and cytotoxic activities of furocoumarins of Ducrosia anethifolia. Pharmaceutical Biology. 2018;56(1):658-664. doi:10.1080/13880209.2018.1548625
- Albayrak G, Demir S, Kose FA, Baykan S. New coumarin glycosides from endemic Prangos heyniae H. Duman & M.F. Watson. Natural Product Research. 2023;37(2):227-239. doi:10.1080/14786419.2021.1961138
- Kuzu B, Ergüç A, Karakuş F, Arzuk E. Design, synthesis, and antiproliferative activities of novel thiazolyl-pyrazole hybrid derivatives. Medicinal Chemistry Research. 2023;32:1690-1700. doi:10.1007/s00044-023-03090-2
- Ergüç A, Karakuş F, Arzuk E, Mutlu N, Orhan H. Role of Oxidative Stress and Reactive Metabolites in Cytotoxicity & Mitotoxicity of Clozapine, Diclofenac and Nifedipine in CHO-K1 Cells In Vitro. Endocrine, Metabolic & Immune Disorders Drug Targets. 2023;(in press). doi: 10.2174/1871530323666230419084613
- Guo R, Zong S, Wu M, Gu J, Yang M. Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2. Cell. 2017;170(6):1247-1257. doi:10.1016/j.cell.2017.07.050
- Du Z, Zhou X, Lai Y, et al. Structure of the human respiratory complex II. Proceedings of the National Academy of Sciences of the United States of America. 2023;120(18). doi:10.1073/pnas.2216713120
- Zong S, Wu M, Gu J, Liu T, Guo R, Yang M. Structure of the intact 14-subunit human cytochrome c oxidase. Cell Research. 2018;28(10):1026-1034. doi:10.1038/s41422-018-0071-1
- Heinz S, Freyberger A, Lawrenz B, Schladt L, Schmuck G, Ellinger-Ziegelbauer H. Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation. Scientific Reports. 2017;7:45465. doi:10.1038/srep45465
- Patra S, Pradhan B, Nayak R, et al. Apoptosis and autophagy modulating dietary phytochemicals in cancer therapeutics: Current evidences and future perspectives. Phytotherapy Research. 2021;35(8):4194-4214. doi:10.1002/ptr.7082
- Sitarek P, Synowiec E, Kowalczyk T, et al. Anticancer Properties of Plectranthus ornatus-Derived Phytochemicals Inducing Apoptosis via Mitochondrial Pathway. International Journal of Molecular Sciences. 2022;23(19):11653. doi:10.3390/ijms231911653
- Xiao J, Wang J, Yuan L, Hao L, Wang D. Study on the mechanism and intervention strategy of sunitinib induced nephrotoxicity. European Journal of Pharmacology. 2019;864:172709. doi:10.1016/j.ejphar.2019.172709
- Jalilian F, Moieni-Arya M, Hosseinzadeh L, Shokoohinia Y. Oxypeucedanin and isoimperatorin extracted from Prangos ferulacea (L.) Lindl protect PC12 pheochromocytoma cells from oxidative stress and apoptosis induced by doxorubicin. Research in Pharmaceutical Sciences. 2021;17(1):12-21. doi:10.4103/1735-5362.329922
- Jalilian F, Moieni-Arya M, Hosseinzadeh L, Shokoohinia Y. Oxypeucedanin and isoimperatorin extracted from Prangos ferulacea (L.) Lindl protect PC12 pheochromocytoma cells from oxidative stress and apoptosis induced by doxorubicin. Research in Pharmaceutical Sciences. 2021;17(1):12-21. doi:10.4103/1735-5362.329922
- Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell. 2015;162(3):540-551. doi:10.1016/j.cell.2015.07.016
- Li Y, Park JS, Deng JH, Bai Y. Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complex. Journal of Bioenergetics and Biomembranes. 2006;38(5-6):283-291. doi:10.1007/s10863-006-9052-z
There are 36 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Oncology and Carcinogenesis (Other) |
| Journal Section | Research Article |
| Authors | |
| Project Number | Çalışma, herhangi bir proje tarafından desteklenmemiştir. |
| Publication Date | December 31, 2023 |
| Submission Date | July 11, 2023 |
| Acceptance Date | October 9, 2023 |
| Published in Issue | Year 2023 Volume: 9 Issue: 3 |
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