Exploring nano curcumin as a potential therapeutic alternative for glioblastoma multiforme via downregulation of growth factors and induction of apoptosis

Year 2025, Volume: 29 Issue: 3, 1145 - 1153, 04.06.2025

Wahyu Widowati , Ahmad Faried Diki Diki Deni Rahmat Annisa Firdaus Sutendi Hanna Sari Widya Kusuma , Nindia Salsabila Mia Dewi Fadhilah Haifa Zahiroh Didik Priyandoko Wahyu Surakusumah , Rizal Azis , Dhanar Septyawan Hadiprasetyo , Rita Tjokropranoto Philip Onggowidjojo

https://doi.org/10.12991/jrespharm.1694300

Abstract

Glioma is a type of brain tumor that start from neuroglial stem cells. Despite advancements in surgery and additional adjuvant therapy such as Temozolomide (TMZ), treating this tumor continues to present a challenge with notable side effects, such as toxicity and resistance to treatment. Therefore, the investigation of natural remedies becomes intriguing. This study examines the potential of nano-particle-formulated curcumin, a compound derived from Curcuma longa L as a promising antitumor agent. The research was carried out in vitro by treating Glioblastoma multiforme (GBM) cell with various concentrations (25, 50, and 100 μg/mL) of nano-particle of curcumin (NC) and TMZ 300 μM. qRT-PCR was employed to assess the relative expression of mRNA Caspase 3 (Casp-3), Insulin-like Growth Factor Binding Protein 2 (IGFBP-2), Epidermal Growth Factor Receptor (EGFR), and Extracellular Signal-Regulated Kinases (ERK). While the proportion of live, necrotic and apoptotic cells was employed utilizing flow cytometry. GBM shows a high expression of growth factors and a low expression of apoptotic gene. The treatment using NC reduced the expression of IGFBP-2, EGFR, and ERK genes, while increasing Casp-3. GBM cells shows higher apoptotic activities and lower necrotic activities after the addition of NC. In comparison to TMZ, NC demonstrates a promise as an anti-tumor agent, particularly for brain tumors, with the optimal dosage identified to be 25 μg/mL.

Keywords

Apoptosis , glioblastoma multiforme , growth factor , nano-curcumin , temozolomide

References

• [1]Georgescu MM. Multi-platform classification of idh-wild-type glioblastoma based on erk/mapk pathway: Diagnostic, prognostic and therapeutic implications. Cancers. 2021; 13(18): 4532. https://dx.doi.org/10.3390/cancers13184532
• [2]Ahir BK, Engelhard HH, Lakka SS. Tumor development and angiogenesis in adult brain tumor: Glioblastoma. Mol Neurobiol. 2020; 57: 2461–2478. https://dx.doi.org/10.1007/s12035-020-01892-8
• [3]Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016; 131: 803–820. https://dx.doi.org/10.1007/s00401-016-1545-1
• [4]Shen F, Song C, Liu Y, Zhang J, Wei Song S. IGFBP2 promotes neural stem cell maintenance and proliferation differentially associated with glioblastoma subtypes. Brain Res. 2019; 1704: 174–186. https://dx.doi.org/10.1016/j.brainres.2018.10.018
• [5]Muir M, Gopakumar S, Traylor J, Lee S, Rao G. Glioblastoma multiforme: Novel therapeutic targets. Expert Opin Ther Targets. 2020; 24(7): 605–614. https://dx.doi.org/10.1080/14728222.2020.1762568
• [6]Georgescu MM. Multi-platform classification of idh-wild-type glioblastoma based on erk/mapk pathway: Diagnostic, prognostic and therapeutic implications. Cancers. 2021; 13(18):4532. https://dx.doi.org/10.3390/cancers131845327.
• [7]Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol. 2022;221(6):e202201159. https://dx.doi.org/10.1083/jcb.202201159
• [8]Rezaei-Tazangi F, Alidadi H, Samimi A, Karimi S, Kahorsandi L. Effects of Wharton’s jelly mesenchymal stem cells-derived secretome on colon carcinoma HT-29 cells. Tissue Cell. 2020; 67: 101413. https://dx.doi.org/10.1016/j.tice.2020.101413
• [9]Barthel L, Hadamitzky M, Dammann P, Schedlowski M, Sure U, Thakur BK, Hetze, S. Glioma: molecular signature and crossroads with tumor microenvironment. Cancer Metastasis Rev. 2022; 41: 53-75. https://dx.doi.org/10.1007/s10555-021-09997-9
• [10]Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, Daldrup-Link HE. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacol Res. 2021; 171: 105780. https://dx.doi.org/10.1016/j.phrs.2021.105780
• [11]Cruz JVR, Batista C, Afonso BH, Alexandre-Moreira MS, Dubois LG, Pontes B, Moura Neto V, Mendes FA. Obstacles to glioblastoma treatment two decades after temozolomide. Cancers. 2022; 14(13): 3203. https://dx.doi.org/10.3390/cancers14133203
• [12]Belter A, Barciszewski J, Barciszewska AM. Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions. PLoS One. 2020;15(2):e0229534. https://dx.doi.org/10.1371/journal.pone.0229534
• [13]Nagahama K, Utsumi T, Kumano T, Maekawa S, Oyama N, Kawakami J. Discovery of a new function of curcumin which enhances its anticancer therapeutic potency. Sci Rep. 2016; 6(1): 30962. https://dx.doi.org/10.1038/srep30962
• [14]Sharifi-Rad J, Rayess Y El, Rizk AA, Sadaka C, Zgheib R, Zam W, Martins N. Turmeric and ıts major compound curcumin on health: Bioactive effects and safety profiles for food, pharmaceutical, biotechnological and medicinal applications. Front Pharmacol. 2020; 11: 550909. https://dx.doi.org/10.3389/fphar.2020.01021
• [15]Astinfeshan M, Rasmi Y, Kheradmand F, Karimipour M, Rahbarghazi R, Aramwit P, Saboory E. Curcumin inhibits angiogenesis in endothelial cells using downregulation of the PI3K/Akt signaling pathway. Food Biosci. 2019; 29: 86–93. https://dx.doi.org/10.1016/j.fbio.2019.04.005
• [16]Tomeh MA, Hadianamrei R, Zhao X. A review of curcumin and its derivatives as anticancer agents. Int J Mol Sci. 2019; 20(5): 1033. https://dx.doi.org/10.3390/ijms20051033
• [17]Fu X, He Y, Li M, Huang Z, Najafi M. Targeting of the tumor microenvironment by curcumin. BioFactors. 2021; 47(6): 914–932. https://dx.doi.org/10.1002/biof.1776
• [18]Boisseau P, Loubaton B. Nanomedicine, nanotechnology in medicine. C R Phys. 2011; 12(7): 620–636. https://dx.doi.org/10.1016/j.crhy.2011.06.001
• [19]Gavas S, Quazi S, Karpiński TM. Nanoparticles for Cancer Therapy: Current Progress and Challenges. Nanoscale Res Lett. 2021; 16(1): 173. https://dx.doi.org/10.1186/s11671-021-03628-6
• [20]Endo H, Inoue I, Masunaka K, Tanaka M, Yano M. Curcumin induces apoptosis in lung cancer cells by 14-3-3 protein-mediated activation of Bad. Biosci Biotechnol Biochem. 2020; 84(12): 2440–2447. https://dx.doi.org/10.1080/09168451.2020.1808443
• [21]Yadav P, Yadav R, Jain S, Vaidya A. Caspase-3: A primary target for natural and synthetic compounds for cancer therapy. Chem Biol Drug Des. 2021; 98(1): 144-165. https://dx.doi.org/10.1111/cbdd.13860
• [22]Aziz MNM, Rahim NFC, Hussin Y, Yeap SK, Masarudin MJ, Mohamad NE, Alitheen NB. Anti-metastatic and anti-angiogenic effects of curcumin analog dk1 on human osteosarcoma cells in vitro. Pharm. 2021; 14(6): 532. https://dx.doi.org/10.3390/ph14060532
• [23]Ashrafizadeh M, Najafi M, Makvandi P, Zarrabi A, Farkhondeh T, Samarghandian S. Versatile role of curcumin and its derivatives in lung cancer therapy. J CellPhysiol. 2020; 235(12): 9241-9268. https://dx.doi.org/10.1002/jcp.29819
• [24]Wang P, Hao X, Li X, Yan Y, Tian W, Xiao L, Dong J. Curcumin inhibits adverse psychological stress-induced proliferation and invasion of glioma cells via down-regulating the ERK/MAPK pathway. J Cell Mol Med. 2021; 25(15): 7190–7203. https://dx.doi.org/10.1111/jcmm.16749
• [25]Chen SR, Cai WP, Dai XJ, Guo HP, Chen GS, Lin GS, Lin RS. Research on miR-126 in glioma targeted regulation of PTEN/PI3K/Akt and MDM2-p53 pathways. Eur Rev Med Pharmacol Sci. 2019; 23: 3461–3470.
• [26]Taylor OG, Brzozowski JS, Skelding KA. Glioblastoma multiforme: An overview of emerging therapeutic targets Front Oncol. 2019; 9: 963. https://dx.doi.org/10.3389/fonc.2019.00963
• [27]Shahcheraghi SH, Tchokonte-Nana V, Lotfi M, Lotfi M, Ghorbani A, Sadeghnia HR. Wnt/beta-catenin and PI3K/Akt/mTOR signaling pathways in glioblastoma: Two main targets for drug design: A Review. Curr Pharm Des. 2020; 26(15): 1729–1741. https://dx.doi.org/10.2174/1381612826666200131100630
• [28]Gong Y, Fan Z, Luo G, Yang C, Huang Q, Fan K, Liu C. The role of necroptosis in cancer biology and therapy. MolCancer. 2019; 18(1): 100. https://dx.doi.org/10.1186/s12943-019-1029-8
• [29]D’Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int. 2019; 43(6): 582–592. https://dx.doi.org/10.1002/cbin.11137
• [30]Ben-Baruch A. Tumor Necrosis Factor α: Taking a personalized road in cancer therapy. Front Immunol. 2022;13:903679. https://dx.doi.org/10.3389/fimmu.2022.903679
• [31]Rahmat D, Farida Y, Brylianto AT, Sumarny R, Kumala S. Antıdıabetıc actıvıty of nanopartıcles contaınıng Javanese Turmerıc rhızome extract: The strategy to change partıcle sıze. Int J App Pharm. 2020; 12(4): 90-93. https://dx.doi.org/10.22159/jap.2020v12i4.36249
• [32]Faried A, Widowati W, Rizal R, Bolly HMB, Halim D, Widodo WS, Satrio HB,Wibowo, Noverina R, Thajono FP, Arifin MZ. Assessment of intratumoral heterogeneity in isolated human primary high-grade glioma: Cluster of differentiation 133 and cluster of differentiation 15 double staining of glioblastoma subpopulations. J Med Sci. 2021; 9: 87–94. https://dx.doi.org/10.3889/oamjms.2021.5516
• [33]Widowati W, Jasaputra DK, Sumitro SB, Widodo MA, Mozef T, Rizal R, Faried A. Effect of interleukins (Il-2, il-15, il-18) on receptors activation and cytotoxic activity of natural killer cells in breast cancer cell. Afr Health Sci. 2020; 20(2): 822–832. https://dx.doi.org/10.4314/ahs.v20i2.36
• [34]Widowati W, Jasaputra DK, Onggowidjaja P, Sumitro SB, Widodo MA, Afifah E, Rihibiha DD, Rizal R, Amalia A, Kusuma HSW, Murti H, Bachtiar I. Effects of conditioned medium of co-culture il-2 induced nk cells and human wharton’s jelly mesenchymal stem cells (Hwjmscs) on apoptotic gene expression in a breast cancer cell line (mcf-7). J Math Fundam Sci. 2019; 51(3): 205–224. https://dx.doi.org/10.5614/j.math.fund.sci.2019.51.3.1
• [35]Widowati W, Wargasetia TL, Rahardja F, Gunanegara RF, Priyandoko D, Gondokesumo ME, Rizal R . hWJMSCs inhibit inflammation and apoptosis in an ARDS cell model. J Taibah Univ Med Sci. 2023; 18(6): 1519–1526. https://dx.doi.org/10.1016%2Fj.jtumed.2023.06.007
• [36]Pujimulyani D, Suryani CL, Setyowati A, Handayani RAS, Arumwardana S, Widowati W, Maruf A. Cosmeceutical potentials of Curcuma mangga Val. extract in human BJ fibroblasts against MMP1, MMP3, and MMP13. Heliyon. 2020;6(9):e04921. https://dx.doi.org/10.1016/j.heliyon.2020.e04921
• [37]Ginting CN, Lister INE, Girsang E, Artie DS, Aviani JK, Widowati W. Apoptotic, MDA, and FGF2 level of quercitrin treatment on hypoxic-induced EA.hy926 cell line. J Rep Pharm Sci. 2021; 10(1): 22–28. https://dx.doi/org/10.4103/jrptps.JRPTPS_70_20
• [38]Widowati W, Gunanegara RF, Wargasetia TL, Kusuma HSW, Arumwardana S, Wahyuni CD, Kim YH. Effect of flavonoids on oxidative stress, apoptosis, and cell markers of peripheral blood-derived endothelial progenitor cells: An in vitro study. Int J App Pharm. 2021; 13: 39–42. https://dx.doi.org/10.22159/ijap.2021.v13s3.07
• [39]Widowati W, Prahastuti S, Tjokropranoto R, Onggowidjaja P, Kusuma HSW, Afifah E, Rizal R. Quercetin prevents chronic kidney disease on mesangial cells model by regulating inflammation, oxidative stress, and TGF-β1/SMADs pathway. PeerJ. 2022; 2:10. https://dx.doi.org/10.7717/peerj.13257