Research Article
Neuroprotective effects of phloretin and phloridzin on paclitaxel-induced neuronal damage in primary neuron cells
Abstract
Purpose: Paclitaxel, is one of the most commonly used chemotherapeutic, causes neuron damage with some serious side effects such as neutropenia and peripheral neuropathy. In current study, we used phloretin and phloridzin to investigate their neuroprotective effects on paclitaxel-induced neuronal damage.
Materials and Methods: The neuroprotective effects of phloretin and phloridzin has been analyzed on cell culture of primary neuron cells and evaluated by testing cell viability, total oxidant and total antioxidant capacities and expression of caspase-3, caspase-9 and TNF-α. Paclitaxel administration caused cell death and significant increase of total oxidant levels and activation of apoptotic genes such as caspase-3, caspase-9 and TNF-α.
Results: Phloretin and phloridzin treatments at micromolar concentrations reduced paclitaxel-induced cell death by increasing total antioxidant levels. Also these two flavonoids protect neuron cells from apoptosis by decreasing caspase-3, caspase-9 and TNF-α gene expression. For this reason, these molecules may recover the oxidative damage, and restore normal cellular conditions.
Conclusion: This study shows the promising neuroprotective ability of the phloretin and phloridzin able to protect neuron cells from injury induced by paclitaxel, actively increasing antioxidant capacity, normalizing oxidant levels and consequently avoiding cell death.
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References
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- 2. Schwab CL, English DP, Roque DM,Santin AD. Taxanes: their impact on gynecologic malignancy. Anticancer Drugs. 2014;25:522-35.
- 3. Bachegowda LS, Makower DF,Sparano JA. Taxanes: impact on breast cancer therapy. Anticancer Drugs. 2014;25:512-21.
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- 6. Letourneau PC,Ressler AH. Inhibition of neurite initiation and growth by taxol. J Cell Biol. 1984;98:1355-62.
- 7. Scuteri A, Nicolini G, Miloso M, Bossi M, Cavaletti G, Windebank AJ, et al. Paclitaxel toxicity in post-mitotic dorsal root ganglion (DRG) cells. Anticancer Res. 2006;26:1065-70.
- 8. Ramezani F, Samadi N,Mostafavi-Pour Z. Sequential Therapy of Breast Cancer Cell Lines with Vitamin C and Quercetin Improves the Efficacy of Chemotherapeutic Drugs. Nutr Cancer. 2017;69:881-91.
- 9. Gosch C, Halbwirth H,Stich K. Phloridzin: biosynthesis, distribution and physiological relevance in plants. Phytochemistry. 2010;71:838-43.
- 10. Li X, Chen B, Xie H, He Y, Zhong D,Chen D. Antioxidant Structure(-)Activity Relationship Analysis of Five Dihydrochalcones. Molecules. 2018;23:
- 11. Karimi-Sales E, Mohaddes G,Alipour MR. Chalcones as putative hepatoprotective agents: Preclinical evidence and molecular mechanisms. Pharmacol Res. 2018;129:177-87.
- 12. Puel C, Quintin A, Mathey J, Obled C, Davicco MJ, Lebecque P, et al. Prevention of bone loss by phloridzin, an apple polyphenol, in ovariectomized rats under inflammation conditions. Calcif Tissue Int. 2005;77:311-8.
- 13. Huang WC, Fang LW,Liou CJ. Phloretin Attenuates Allergic Airway Inflammation and Oxidative Stress in Asthmatic Mice. Front Immunol. 2017;8:134.
- 14. Barreca D, Curro M, Bellocco E, Ficarra S, Lagana G, Tellone E, et al. Neuroprotective effects of phloretin and its glycosylated derivative on rotenone-induced toxicity in human SH-SY5Y neuronal-like cells. Biofactors. 2017;43:549-57.
- 15. Un H, Ugan RA, Gurbuz MA, Bayir Y, Kahramanlar A, Kaya G, et al. Phloretin and phloridzin guard against cisplatin-induced nephrotoxicity in mice through inhibiting oxidative stress and inflammation. Life Sciences. 2021;266:118869.
- 16. Harun Ü,Ugan RA. Protective effects of phloretin and phloridzin on indomethacin-induced gastric ulcers in mice: characterization of potential molecular mechanisms. Cukurova Medical Journal. 2020;45:1459-66.
- 17. Xu M, Gu W, Shen Z,Wang F. Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway. Med Sci Monit. 2018;24:6551-58.
- 18. Chen Y, Liu J, Geng S, Liu Y, Ma H, Zheng J, et al. Lipase-catalyzed synthesis mechanism of tri-acetylated phloridzin and its antiproliferative activity against HepG2 cancer cells. Food Chem. 2019;277:186-94.
- 19. Yayla M, Binnetoglu D, Demirbag C,Kilicle Aksu P. Protective Effects of Pomegranate Peel Extract on Paclitaxel Induced Primary Neuron Damage in Rats. Kafkas J Med Sci 2018;8:149-57.
- 20. Ugan RA,Un H. The Protective Roles of Butein on Indomethacin Induced Gastric Ulcer in Mice. The Eurasian Journal of Medicine. 2020;52:265.
- 21. Livak KJ,Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402-8.
- 22. Shemesh OA,Spira ME. Paclitaxel induces axonal microtubules polar reconfiguration and impaired organelle transport: implications for the pathogenesis of paclitaxel-induced polyneuropathy. Acta Neuropathol. 2010;119:235-48.
- 23. Wang MS, Davis AA, Culver DG,Glass JD. WldS mice are resistant to paclitaxel (taxol) neuropathy. Ann Neurol. 2002;52:442-7.
- 24. Yang IH, Siddique R, Hosmane S, Thakor N,Hoke A. Compartmentalized microfluidic culture platform to study mechanism of paclitaxel-induced axonal degeneration. Exp Neurol. 2009;218:124-8.
- 25. Fotakis G,Timbrell JA. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol Lett. 2006;160:171-7.
- 26. van de Loosdrecht AA, Beelen RH, Ossenkoppele GJ, Broekhoven MG,Langenhuijsen MM. A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. J Immunol Methods. 1994;174:311-20.
- 27. Cetin D, Hacimuftuoglu A, Tatar A, Turkez H,Togar B. The in vitro protective effect of salicylic acid against paclitaxel and cisplatin-induced neurotoxicity. Cytotechnology. 2016;68:1361-7.
- 28. Duggett NA, Griffiths LA, McKenna OE, de Santis V, Yongsanguanchai N, Mokori EB, et al. Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy. Neuroscience. 2016;333:13-26.
- 29. Kim HK, Zhang YP, Gwak YS,Abdi S. Phenyl N-tert-butylnitrone, a free radical scavenger, reduces mechanical allodynia in chemotherapy-induced neuropathic pain in rats. Anesthesiology. 2010;112:432-9.
- 30. Doyle T, Chen Z, Muscoli C, Bryant L, Esposito E, Cuzzocrea S, et al. Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. J Neurosci. 2012;32:6149-60.
- 31. Motor S, Ozturk S, Ozcan O, Gurpinar AB, Can Y, Yuksel R, et al. Evaluation of total antioxidant status, total oxidant status and oxidative stress index in patients with alopecia areata. Int J Clin Exp Med. 2014;7:1089-93.
- 32. Aslan R, Kutlu R, Civi S,Tasyurek E. The correlation of the total antioxidant status (TAS), total oxidant status (TOS) and paraoxonase activity (PON1) with smoking. Clin Biochem. 2014;47:393-7.
- 33. Basarslan SK, Osun A, Senol S, Korkmaz M, Ozkan U,Kaplan I. Protective Effects of Intralipid and Caffeic Acid Phenyl Esther (CAPE) on Neurotoxicity Induced by Ethanol in Rats. Turk Neurosurg. 2017;27:66-73.
- 34. MacEwan DJ. TNF ligands and receptors--a matter of life and death. Br J Pharmacol. 2002;135:855-75.
- 35. Saritemur M, Un H, Cadirci E, Karakus E, Akpinar E, Halici Z, et al. Tnf-alpha inhibition by infliximab as a new target for the prevention of glycerol-contrast-induced nephropathy. Environ Toxicol Pharmacol. 2015;39:577-88.
- 36. Bogdan C,Ding A. Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages. J Leukoc Biol. 1992;52:119-21.
- 37. MacEwan DJ. TNF receptor subtype signalling: differences and cellular consequences. Cell Signal. 2002;14:477-92.
- 38. Wood SC, Tang X,Tesfamariam B. Paclitaxel potentiates inflammatory cytokine-induced prothrombotic molecules in endothelial cells. J Cardiovasc Pharmacol. 2010;55:276-85.
- 39. Wu Z, Wang S, Wu I, Mata M,Fink DJ. Activation of TLR-4 to produce tumour necrosis factor-alpha in neuropathic pain caused by paclitaxel. Eur J Pain. 2015;19:889-98.
- 40. Jordan MA,Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4:253-65.
- 41. Ashkenazi A. Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions. J Clin Invest. 2015;125:487-9.
- 42. Obiorah I, Sengupta S, Fan P,Jordan VC. Delayed triggering of oestrogen induced apoptosis that contrasts with rapid paclitaxel-induced breast cancer cell death. Br J Cancer. 2014;110:1488-96.
- 43. Kim B, Srivastava SK,Kim SH. Caspase-9 as a therapeutic target for treating cancer. Expert Opin Ther Targets. 2015;19:113-27.
- 44. Tanimukai H, Kanayama D, Omi T, Takeda M,Kudo T. Paclitaxel induces neurotoxicity through endoplasmic reticulum stress. Biochem Biophys Res Commun. 2013;437:151-5.
- 45. Melli G, Taiana M, Camozzi F, Triolo D, Podini P, Quattrini A, et al. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol. 2008;214:276-84.
- 46. Kong L, Hu W, Lu C, Cheng K,Tang M. Mechanisms underlying nickel nanoparticle induced reproductive toxicity and chemo-protective effects of vitamin C in male rats. Chemosphere. 2019;218:259-65.
Floretin ve floridzin'in primer nöron hücrelerinde paklitaksel ile indüklenen nöron hasarındaki koruyucu etkileri
Abstract
Amaç: Kemoterapide sıklıkla kullanılan paklitaksel, nötropeni ve periferik nöropati gibi bazı ciddi yan etkilerle nöron hasarına neden olur. Biz bu çalışmada, floretin ve floridzin’ in paklitaksel kaynaklı nöronal hasar üzerindeki nöroprotektif etkilerini araştırdık.
Gereç ve Yöntem: Floretin ve floridzin’ in nöroprotektif etkileri primer nöron hücreleri üzerindeki etkileri, hücre canlılığı, total oksidan ve antioksidan kapasiteleri ve kaspaz-3, kaspaz-9 ve TNF-α ekspresyonu test edilerek değerlendirilmiştir.
Bulgular: Paklitaksel uygulaması hücre ölümüne, toplam oksidan seviyelerinin önemli ölçüde artmasına ve kaspaz-3, kaspaz-9 ve TNF-α gibi apoptotik genlerin aktivasyonuna neden oldu. Mikromolar konsantrasyonlardaki floretin ve floridzin tedavileri, toplam antioksidan seviyelerini artırarak paklitaksel kaynaklı hücre ölümünü azalttı. Ayrıca bu iki flavonoid, kaspaz-3, kaspaz-9 ve TNF-α gen ekspresyonlarını azaltarak nöron hücrelerini apoptozdan korudu. Bu nedenle, bu moleküller oksidatif hasardan geri kazanımı indükleyebilir ve normal hücresel koşulları düzenleyebilir.
Sonuç: Bu çalışma, floretin ve floridzin’ in nöron hücrelerini paklitaksel kaynaklı hücre hasarından koruyabilen, antioksidan kapasitesini aktif olarak arttıran, oksidan seviyelerini normalleştiren ve sonuç olarak hücre ölümünü önlemede umut verici nöroprotektif potansiyelini göstermektedir.
Keywords
Project Number
-
References
- 1. Gewirtz DA, Bristol ML,Yalowich JC. Toxicity issues in cancer drug development. Curr Opin Investig Drugs. 2010;11:612-4.
- 2. Schwab CL, English DP, Roque DM,Santin AD. Taxanes: their impact on gynecologic malignancy. Anticancer Drugs. 2014;25:522-35.
- 3. Bachegowda LS, Makower DF,Sparano JA. Taxanes: impact on breast cancer therapy. Anticancer Drugs. 2014;25:512-21.
- 4. Joshi M, Liu X,Belani CP. Taxanes, past, present, and future impact on non-small cell lung cancer. Anticancer Drugs. 2014;25:571-83.
- 5. Alqahtani FY, Aleanizy FS, El Tahir E, Alkahtani HM,AlQuadeib BT. Paclitaxel. Profiles Drug Subst Excip Relat Methodol. 2019;44:205-38.
- 6. Letourneau PC,Ressler AH. Inhibition of neurite initiation and growth by taxol. J Cell Biol. 1984;98:1355-62.
- 7. Scuteri A, Nicolini G, Miloso M, Bossi M, Cavaletti G, Windebank AJ, et al. Paclitaxel toxicity in post-mitotic dorsal root ganglion (DRG) cells. Anticancer Res. 2006;26:1065-70.
- 8. Ramezani F, Samadi N,Mostafavi-Pour Z. Sequential Therapy of Breast Cancer Cell Lines with Vitamin C and Quercetin Improves the Efficacy of Chemotherapeutic Drugs. Nutr Cancer. 2017;69:881-91.
- 9. Gosch C, Halbwirth H,Stich K. Phloridzin: biosynthesis, distribution and physiological relevance in plants. Phytochemistry. 2010;71:838-43.
- 10. Li X, Chen B, Xie H, He Y, Zhong D,Chen D. Antioxidant Structure(-)Activity Relationship Analysis of Five Dihydrochalcones. Molecules. 2018;23:
- 11. Karimi-Sales E, Mohaddes G,Alipour MR. Chalcones as putative hepatoprotective agents: Preclinical evidence and molecular mechanisms. Pharmacol Res. 2018;129:177-87.
- 12. Puel C, Quintin A, Mathey J, Obled C, Davicco MJ, Lebecque P, et al. Prevention of bone loss by phloridzin, an apple polyphenol, in ovariectomized rats under inflammation conditions. Calcif Tissue Int. 2005;77:311-8.
- 13. Huang WC, Fang LW,Liou CJ. Phloretin Attenuates Allergic Airway Inflammation and Oxidative Stress in Asthmatic Mice. Front Immunol. 2017;8:134.
- 14. Barreca D, Curro M, Bellocco E, Ficarra S, Lagana G, Tellone E, et al. Neuroprotective effects of phloretin and its glycosylated derivative on rotenone-induced toxicity in human SH-SY5Y neuronal-like cells. Biofactors. 2017;43:549-57.
- 15. Un H, Ugan RA, Gurbuz MA, Bayir Y, Kahramanlar A, Kaya G, et al. Phloretin and phloridzin guard against cisplatin-induced nephrotoxicity in mice through inhibiting oxidative stress and inflammation. Life Sciences. 2021;266:118869.
- 16. Harun Ü,Ugan RA. Protective effects of phloretin and phloridzin on indomethacin-induced gastric ulcers in mice: characterization of potential molecular mechanisms. Cukurova Medical Journal. 2020;45:1459-66.
- 17. Xu M, Gu W, Shen Z,Wang F. Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway. Med Sci Monit. 2018;24:6551-58.
- 18. Chen Y, Liu J, Geng S, Liu Y, Ma H, Zheng J, et al. Lipase-catalyzed synthesis mechanism of tri-acetylated phloridzin and its antiproliferative activity against HepG2 cancer cells. Food Chem. 2019;277:186-94.
- 19. Yayla M, Binnetoglu D, Demirbag C,Kilicle Aksu P. Protective Effects of Pomegranate Peel Extract on Paclitaxel Induced Primary Neuron Damage in Rats. Kafkas J Med Sci 2018;8:149-57.
- 20. Ugan RA,Un H. The Protective Roles of Butein on Indomethacin Induced Gastric Ulcer in Mice. The Eurasian Journal of Medicine. 2020;52:265.
- 21. Livak KJ,Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402-8.
- 22. Shemesh OA,Spira ME. Paclitaxel induces axonal microtubules polar reconfiguration and impaired organelle transport: implications for the pathogenesis of paclitaxel-induced polyneuropathy. Acta Neuropathol. 2010;119:235-48.
- 23. Wang MS, Davis AA, Culver DG,Glass JD. WldS mice are resistant to paclitaxel (taxol) neuropathy. Ann Neurol. 2002;52:442-7.
- 24. Yang IH, Siddique R, Hosmane S, Thakor N,Hoke A. Compartmentalized microfluidic culture platform to study mechanism of paclitaxel-induced axonal degeneration. Exp Neurol. 2009;218:124-8.
- 25. Fotakis G,Timbrell JA. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol Lett. 2006;160:171-7.
- 26. van de Loosdrecht AA, Beelen RH, Ossenkoppele GJ, Broekhoven MG,Langenhuijsen MM. A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. J Immunol Methods. 1994;174:311-20.
- 27. Cetin D, Hacimuftuoglu A, Tatar A, Turkez H,Togar B. The in vitro protective effect of salicylic acid against paclitaxel and cisplatin-induced neurotoxicity. Cytotechnology. 2016;68:1361-7.
- 28. Duggett NA, Griffiths LA, McKenna OE, de Santis V, Yongsanguanchai N, Mokori EB, et al. Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy. Neuroscience. 2016;333:13-26.
- 29. Kim HK, Zhang YP, Gwak YS,Abdi S. Phenyl N-tert-butylnitrone, a free radical scavenger, reduces mechanical allodynia in chemotherapy-induced neuropathic pain in rats. Anesthesiology. 2010;112:432-9.
- 30. Doyle T, Chen Z, Muscoli C, Bryant L, Esposito E, Cuzzocrea S, et al. Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. J Neurosci. 2012;32:6149-60.
- 31. Motor S, Ozturk S, Ozcan O, Gurpinar AB, Can Y, Yuksel R, et al. Evaluation of total antioxidant status, total oxidant status and oxidative stress index in patients with alopecia areata. Int J Clin Exp Med. 2014;7:1089-93.
- 32. Aslan R, Kutlu R, Civi S,Tasyurek E. The correlation of the total antioxidant status (TAS), total oxidant status (TOS) and paraoxonase activity (PON1) with smoking. Clin Biochem. 2014;47:393-7.
- 33. Basarslan SK, Osun A, Senol S, Korkmaz M, Ozkan U,Kaplan I. Protective Effects of Intralipid and Caffeic Acid Phenyl Esther (CAPE) on Neurotoxicity Induced by Ethanol in Rats. Turk Neurosurg. 2017;27:66-73.
- 34. MacEwan DJ. TNF ligands and receptors--a matter of life and death. Br J Pharmacol. 2002;135:855-75.
- 35. Saritemur M, Un H, Cadirci E, Karakus E, Akpinar E, Halici Z, et al. Tnf-alpha inhibition by infliximab as a new target for the prevention of glycerol-contrast-induced nephropathy. Environ Toxicol Pharmacol. 2015;39:577-88.
- 36. Bogdan C,Ding A. Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages. J Leukoc Biol. 1992;52:119-21.
- 37. MacEwan DJ. TNF receptor subtype signalling: differences and cellular consequences. Cell Signal. 2002;14:477-92.
- 38. Wood SC, Tang X,Tesfamariam B. Paclitaxel potentiates inflammatory cytokine-induced prothrombotic molecules in endothelial cells. J Cardiovasc Pharmacol. 2010;55:276-85.
- 39. Wu Z, Wang S, Wu I, Mata M,Fink DJ. Activation of TLR-4 to produce tumour necrosis factor-alpha in neuropathic pain caused by paclitaxel. Eur J Pain. 2015;19:889-98.
- 40. Jordan MA,Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4:253-65.
- 41. Ashkenazi A. Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions. J Clin Invest. 2015;125:487-9.
- 42. Obiorah I, Sengupta S, Fan P,Jordan VC. Delayed triggering of oestrogen induced apoptosis that contrasts with rapid paclitaxel-induced breast cancer cell death. Br J Cancer. 2014;110:1488-96.
- 43. Kim B, Srivastava SK,Kim SH. Caspase-9 as a therapeutic target for treating cancer. Expert Opin Ther Targets. 2015;19:113-27.
- 44. Tanimukai H, Kanayama D, Omi T, Takeda M,Kudo T. Paclitaxel induces neurotoxicity through endoplasmic reticulum stress. Biochem Biophys Res Commun. 2013;437:151-5.
- 45. Melli G, Taiana M, Camozzi F, Triolo D, Podini P, Quattrini A, et al. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol. 2008;214:276-84.
- 46. Kong L, Hu W, Lu C, Cheng K,Tang M. Mechanisms underlying nickel nanoparticle induced reproductive toxicity and chemo-protective effects of vitamin C in male rats. Chemosphere. 2019;218:259-65.
There are 46 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Research |
| Authors | |
| Project Number | - |
| Publication Date | June 30, 2021 |
| Acceptance Date | March 4, 2021 |
| Published in Issue | Year 2021 Volume: 46 Issue: 2 |
Cited By
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https://doi.org/10.1016/j.ejphar.2021.174645
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