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Kurkuminin U87 Glioblastoma Hücrelerinde Kanser Kök Hücre Belirteçlerine ve P Glikoprotein Aracılı İlaç Direncine Olan Etkisi

Year 2025, Volume: 8 Issue: 3, 138 - 147, 28.10.2025
https://doi.org/10.26650/JARHS2025-1746753

Abstract

Amaç: Curcuma longa rizomlarından türetilen polifenolik bir bileşik olan kurkumin; anti-inflamatuar, antioksidan ve antikanser aktiviteler dahil olmak üzere çok çeşitli farmakolojik özelliklere sahiptir. Yaygın bir şekilde geleneksel tıbbi uygulamaları tercih edilmesine rağmen özellikle glioblastoma multiforme'deki (GBM) terapötik potansiyeli yeterince araştırılmamıştır. Bu çalışma kurkuminin glioblastoma proliferasyonu, apoptoz, kanser kök hücresi (CSC) belirteçlerinin ifadesi, ilaç direnci mekanizmaları ve hücre döngüsü düzenlemesi üzerindeki etkilerini incelemeyi ve GBM tedavisinde yeni bir yardımcı terapötik ajan olarak potansiyelini belirlemeyi amaçlamaktadır.

Gereç ve Yöntemler: Kurkuminin sitotoksik etkisi MTT yöntemiyle gösterildi. Apoptoz, Annexin V/PI boyaması kullanılarak akış sitometrisinde çalışıldı. Hücre döngüsündeki değişiklikler incelendi. CSC belirteçlerinden CD44, CD24, CD133 ve çoklu ilaç direnci taşıyıcısı P-glikoproteinin (Pgp) ifadesi akış sitometrisi ile belirlendi.

Bulgular: Kurkuminin, apoptozu teşvik ederken U87 glioblastoma hücre hatlarının çoğalmasını engellediği bulundu. Hücreleri G2/M fazında etkili bir şekilde durdurdu. Kurkumin ayrıca tümör agresifliği ve tedavi direncinde rol oynayan CD44 ve CD133 dahil olmak üzere CSC belirteçlerinin ifadesini de düzenledi. Ayrıca, kurkumin düşük konsantrasyonlarda P-glikoproteinin ifadesini engellediği görüldü.

Sonuç: Kurkumin, çoğalmanın inhibisyonu, apoptozisin indüklenmesi, CSC belirteçlerinin modülasyonu ve ilaç direnci yollarına müdahale dahil olmak üzere birden fazla mekanizma yoluyla glioblastomada ümit verici antikanser aktivite göstermektedir. Bu bulgular kurkuminin GBM’de adjuvan ajan olarak potansiyelini ortaya koymakta olup daha fazla araştırma yapılmasını gerektirmektedir.

References

  • Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, et al. NABTT CNS Consortium: Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 201016:2443-9. google scholar
  • Kingwell, K. New targets for drug delivery across the BBB. Nat Rev Drug Discov 2016;15:84-5. google scholar
  • Alimohammadi E, Bagheri SR, Taheri S, Dayani M, Abdi A. The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma multiforme: a meta-analysis and systematic review. Oncol Rev 2020;14(1):461. google scholar
  • Mousavi SM, Hosseindoost S, Mahdian SMA, Vousooghi N, Rajabi A, Jafari A, et al. Exosomes released from U87 glioma cells treated with curcumin and/ or temozolomide produce apoptosis in naive U87 cells. Pathol Res Pract 2023;245:154427. google scholar
  • Shehzad A, Wahid F, Lee YS. Curcumin in cancer chemoprevention: Molecular targets, pharmacokinetics, bioavailability, and clinical trials. Arch Der Pharm 2010;343:489-99. google scholar
  • Giordano A, Tommonaro G. Curcumin and cancer. Nutrients 2019;5-11(10):2376. google scholar
  • Cheng C, Jiao JT, Qian Y, Guo XY, Huang J, Dai MC, et al. Curcumin induces G2/ M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells. Mol Med Rep 2016;13(5):3763-70. google scholar
  • Zhuang W, Long L, Zheng B, Ji W, Yang N, Zhang Q, et al. Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Sci 2012;103:684-90. google scholar
  • Kumar A, Ahuja A, Ali J, Baboota S. Curcumin-loaded lipid nanocarrier for improving bioavailability, stability and cytotoxicity against malignant glioma cells. Drug Deliv 2016;23:214-29. google scholar
  • Hartheimer JS, Park S, Rao SS, Kim Y. Targeting hyaluronan interactions for glioblastoma stem cell therapy. Cancer Microenviron 2019;12(1):47-56. google scholar
  • Kapoor-Narula U, Lenka N. Elucidating the anti-tumorigenic efficacy of oltipraz, a dithiolethione, in glioblastoma. Cells 2022;11(19):3057. google scholar
  • Kolliopoulos C, Ali MM, Castillejo-Lopez C, Heldin CH, Heldin P. CD44 depletion in Glioblastoma cells suppresses growth and stemness and induces senescence. Cancers (Basel) 2022;14(15):3747. google scholar
  • Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol 2018;11(1):64. google scholar
  • Wang Z, Liu F, Liao W, Yu L, Hu Z, Li M, et al. Curcumin suppresses glioblastoma cell proliferation by p-AKT/mTOR pathway and increases the PTEN expression. Arch Biochem Biophys 2020;15(689):108412. google scholar
  • Zanotto-Filho A, Braganhol E, Edelweiss MI, Behr GA, Zanin R, Schröder R, et al. The curry spice curcumin selectively inhibits cancer cells growth in vitro and in preclinical model of glioblastoma. J Nutr Biochem 2012;23:591-601. google scholar
  • Lee YQ, Rajadurai P, Abas F, Othman I, Naidu R. Proteomic analysis on antiproliferative and apoptosis effects of curcumin analog, 1,5-bis(4-hydroxy-3-methyoxyphenyl)-1,4-pentadiene-3-one-treated human glioblastoma and neuroblastoma cells. Front Mol Biosci 2021;30(8):645856. google scholar
  • Huls M, Russel FG, Masereeuw R. The role of ATP binding cassette transporters in tissue defense and organ regeneration. J Pharmacol Exp Ther 2009;328:3-9. google scholar
  • Sharom FJ. The P-glycoprotein multidrug transporter. Essays Biochem 2011;50:161-78. google scholar
  • Anuchapreeda, S, Leechanachai, P, Smith, MM, Ambudkar, SV, Limtrakul, PN. Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochemical Pharmacol 2002;64(4):573-82. google scholar
  • Chearwae W, Anuchapreeda S, Nandigama K, Ambudkar SV, Limtrakul P. Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder. Biochemical Pharmacol 2004;68(10):2043-52. google scholar
  • Fathy Abd-Ellatef GE, Gazzano E, Chirio D, Hamed AR, Belisario DC, Zuddas C, et. al. Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells. Pharmaceutics 2020;12(2):96. google scholar
  • Zhang X, Chen Q, Wang Y, Peng W, Cai H. Effects of curcumin on ion channels and transporters. Frontiers Physiol 2014;5:94. google scholar
  • Walker BC, Mittal S. Antitumor Activity of Curcumin in Glioblastoma. Int J Mol Sci 2020;21(24):9435. google scholar
  • Nautiyal J, Kanwar SS, Yu Y, Majumdar AP. Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. J Mol Signal 2011;6:7. google scholar
  • Buhrmann C, Yazdi M, Dezfouli A, Sahraneshin F, Ebrahimi S, Ghaffari S, et al. Significant decrease in the viability and tumor stem cell marker expression in tumor cell lines treated with curcumin. J Herbal Med 2020;22:100339. google scholar
  • Zhang N, Gao M, Wang Z, Zhang J, Cui W, Li J, et. al. Curcumin reverses doxorubicin resistance in colon cancer cells at the metabolic level. J Pharm Biomed Anal 2021;15;(201):114129. google scholar
  • Rui H, Hao Y, Fengcheng H, Shaowu T. Strategy to enhance efficacy of doxorubicin by curcumin as a potent Pgp inhibitor in gastric cancer. Biomed Res 2017;28(3):1231-6. google scholar
  • Gersey ZC, Rodriguez GA, Barbarite E, Sanchez A, Walters WM, Ohaeto KC, et al. Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species. BMC Cancer, 2017;17(1):99. google scholar
  • Razali NSC, Lam KW, Rajab NF, Jamal ARA, Kamaludin NF, Chan KM. Curcumin piperidone derivatives induce caspase-dependent apoptosis and suppress miRNA-21 expression in LN-18 human glioblastoma cells. Genes Environment, 2024;46(1):4. google scholar

Effects of Curcumin on Cancer Stem Cell Markers and P-Glycoprotein-Mediated Drug Resistance in U87 Glioblastoma Cells

Year 2025, Volume: 8 Issue: 3, 138 - 147, 28.10.2025
https://doi.org/10.26650/JARHS2025-1746753

Abstract

Objective: Curcumin, a polyphenolic compound derived from the rhizomes of Curcuma longa, possesses a wide array of pharmacological properties, including anti-inflammatory, antioxidant, and anticancer activities. Despite its traditional medicinal applications, its therapeutic potential, particularly in glioblastoma multiforme (GBM), remains insufficiently explored. This study seeks to examine the effects of curcumin on glioblastoma proliferation, apoptosis, cancer stem cell (CSC) marker expression, drug resistance mechanisms, and cell cycle regulation, with the aim of identifying its potential as a novel adjunct therapeutic agent in GBM treatment.

Material and Methods: We conducted a cytotoxicity assay using thiazolyl blue tetrazolium bromide (MTT). Apoptosis was assessed through annexin/PI staining. Cell cycle analysis was performed. Flow cytometry was used to analyse the staining of CD44/CD24/ CD133 and the multidrug resistance transporter, P-glycoprotein (Pgp).

Results: Curcumin was found to inhibit the proliferation of U87 glioblastoma cell lines while promoting apoptosis. Cells were arrested in the G2/M phase effectively. Curcumin also modulated the expression of CSC markers, including CD44 and CD133, which are implicated in tumour aggressiveness and treatment resistance. In addition, curcumin inhibited the expression of P-glycoprotein at low concentrations.

Conclusion: Curcumin exhibits promising anticancer activity in GBM through multiple mechanisms, including the inhibition of proliferation, induction of apoptosis, modulation of CSC markers, and interference with drug resistance pathways. These findings suggest curcumin’s potential as an adjuvant therapeutic agent in GBM management, warranting further investigation.

References

  • Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, et al. NABTT CNS Consortium: Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 201016:2443-9. google scholar
  • Kingwell, K. New targets for drug delivery across the BBB. Nat Rev Drug Discov 2016;15:84-5. google scholar
  • Alimohammadi E, Bagheri SR, Taheri S, Dayani M, Abdi A. The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma multiforme: a meta-analysis and systematic review. Oncol Rev 2020;14(1):461. google scholar
  • Mousavi SM, Hosseindoost S, Mahdian SMA, Vousooghi N, Rajabi A, Jafari A, et al. Exosomes released from U87 glioma cells treated with curcumin and/ or temozolomide produce apoptosis in naive U87 cells. Pathol Res Pract 2023;245:154427. google scholar
  • Shehzad A, Wahid F, Lee YS. Curcumin in cancer chemoprevention: Molecular targets, pharmacokinetics, bioavailability, and clinical trials. Arch Der Pharm 2010;343:489-99. google scholar
  • Giordano A, Tommonaro G. Curcumin and cancer. Nutrients 2019;5-11(10):2376. google scholar
  • Cheng C, Jiao JT, Qian Y, Guo XY, Huang J, Dai MC, et al. Curcumin induces G2/ M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells. Mol Med Rep 2016;13(5):3763-70. google scholar
  • Zhuang W, Long L, Zheng B, Ji W, Yang N, Zhang Q, et al. Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Sci 2012;103:684-90. google scholar
  • Kumar A, Ahuja A, Ali J, Baboota S. Curcumin-loaded lipid nanocarrier for improving bioavailability, stability and cytotoxicity against malignant glioma cells. Drug Deliv 2016;23:214-29. google scholar
  • Hartheimer JS, Park S, Rao SS, Kim Y. Targeting hyaluronan interactions for glioblastoma stem cell therapy. Cancer Microenviron 2019;12(1):47-56. google scholar
  • Kapoor-Narula U, Lenka N. Elucidating the anti-tumorigenic efficacy of oltipraz, a dithiolethione, in glioblastoma. Cells 2022;11(19):3057. google scholar
  • Kolliopoulos C, Ali MM, Castillejo-Lopez C, Heldin CH, Heldin P. CD44 depletion in Glioblastoma cells suppresses growth and stemness and induces senescence. Cancers (Basel) 2022;14(15):3747. google scholar
  • Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol 2018;11(1):64. google scholar
  • Wang Z, Liu F, Liao W, Yu L, Hu Z, Li M, et al. Curcumin suppresses glioblastoma cell proliferation by p-AKT/mTOR pathway and increases the PTEN expression. Arch Biochem Biophys 2020;15(689):108412. google scholar
  • Zanotto-Filho A, Braganhol E, Edelweiss MI, Behr GA, Zanin R, Schröder R, et al. The curry spice curcumin selectively inhibits cancer cells growth in vitro and in preclinical model of glioblastoma. J Nutr Biochem 2012;23:591-601. google scholar
  • Lee YQ, Rajadurai P, Abas F, Othman I, Naidu R. Proteomic analysis on antiproliferative and apoptosis effects of curcumin analog, 1,5-bis(4-hydroxy-3-methyoxyphenyl)-1,4-pentadiene-3-one-treated human glioblastoma and neuroblastoma cells. Front Mol Biosci 2021;30(8):645856. google scholar
  • Huls M, Russel FG, Masereeuw R. The role of ATP binding cassette transporters in tissue defense and organ regeneration. J Pharmacol Exp Ther 2009;328:3-9. google scholar
  • Sharom FJ. The P-glycoprotein multidrug transporter. Essays Biochem 2011;50:161-78. google scholar
  • Anuchapreeda, S, Leechanachai, P, Smith, MM, Ambudkar, SV, Limtrakul, PN. Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochemical Pharmacol 2002;64(4):573-82. google scholar
  • Chearwae W, Anuchapreeda S, Nandigama K, Ambudkar SV, Limtrakul P. Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder. Biochemical Pharmacol 2004;68(10):2043-52. google scholar
  • Fathy Abd-Ellatef GE, Gazzano E, Chirio D, Hamed AR, Belisario DC, Zuddas C, et. al. Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells. Pharmaceutics 2020;12(2):96. google scholar
  • Zhang X, Chen Q, Wang Y, Peng W, Cai H. Effects of curcumin on ion channels and transporters. Frontiers Physiol 2014;5:94. google scholar
  • Walker BC, Mittal S. Antitumor Activity of Curcumin in Glioblastoma. Int J Mol Sci 2020;21(24):9435. google scholar
  • Nautiyal J, Kanwar SS, Yu Y, Majumdar AP. Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. J Mol Signal 2011;6:7. google scholar
  • Buhrmann C, Yazdi M, Dezfouli A, Sahraneshin F, Ebrahimi S, Ghaffari S, et al. Significant decrease in the viability and tumor stem cell marker expression in tumor cell lines treated with curcumin. J Herbal Med 2020;22:100339. google scholar
  • Zhang N, Gao M, Wang Z, Zhang J, Cui W, Li J, et. al. Curcumin reverses doxorubicin resistance in colon cancer cells at the metabolic level. J Pharm Biomed Anal 2021;15;(201):114129. google scholar
  • Rui H, Hao Y, Fengcheng H, Shaowu T. Strategy to enhance efficacy of doxorubicin by curcumin as a potent Pgp inhibitor in gastric cancer. Biomed Res 2017;28(3):1231-6. google scholar
  • Gersey ZC, Rodriguez GA, Barbarite E, Sanchez A, Walters WM, Ohaeto KC, et al. Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species. BMC Cancer, 2017;17(1):99. google scholar
  • Razali NSC, Lam KW, Rajab NF, Jamal ARA, Kamaludin NF, Chan KM. Curcumin piperidone derivatives induce caspase-dependent apoptosis and suppress miRNA-21 expression in LN-18 human glioblastoma cells. Genes Environment, 2024;46(1):4. google scholar
There are 29 citations in total.

Details

Primary Language English
Subjects Clinical Oncology
Journal Section Research Article
Authors

Esra Nazlıgül 0000-0002-7383-8619

Bilge Özerman Edis 0000-0002-3499-0474

Mustafa Nuri Yenerel 0000-0002-6473-1342

Başak Günçer 0000-0002-0597-4571

Submission Date July 20, 2025
Acceptance Date September 30, 2025
Publication Date October 28, 2025
Published in Issue Year 2025 Volume: 8 Issue: 3

Cite

MLA Nazlıgül, Esra et al. “Effects of Curcumin on Cancer Stem Cell Markers and P-Glycoprotein-Mediated Drug Resistance in U87 Glioblastoma Cells”. Journal of Advanced Research in Health Sciences, vol. 8, no. 3, 2025, pp. 138-47, doi:10.26650/JARHS2025-1746753.