Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study
The treatment of glioblastoma multiforme (GBM) is challenging owing to its localization in the brain, the limited capacity of brain cells to repair, resistance to conventional therapy, and its aggressiveness. Curcumin has anticancer activity against aggressive cancers, such as leukemia, and GBM; how...
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| Format: | Article |
| Language: | English |
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Springer
2022
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| Online Access: | https://repository.ugm.ac.id/278771/1/Hermawan-3_FA.pdf |
| _version_ | 1826050318496956416 |
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| author | Hermawan, Adam Wulandari, Febri Hanif, Naufa Utomo, Rohmad Yudi Jenie, Riris Istighfari Ikawati, Muthi' Tafrihani, Ahmad Syauqy |
| author_facet | Hermawan, Adam Wulandari, Febri Hanif, Naufa Utomo, Rohmad Yudi Jenie, Riris Istighfari Ikawati, Muthi' Tafrihani, Ahmad Syauqy |
| author_sort | Hermawan, Adam |
| collection | UGM |
| description | The treatment of glioblastoma multiforme (GBM) is challenging owing to its localization in the brain, the limited capacity of brain cells to repair, resistance to conventional therapy, and its aggressiveness. Curcumin has anticancer activity against aggressive cancers, such as leukemia, and GBM; however, its application is limited by its low solubility and bioavailability. Chemoprevention curcumin analog 1.1 (CCA‑1.1), a curcumin analog, has better solubility and stability than those of curcumin. In this study, we explored potential targets of CCA‑1.1 in GBM (PTCGs) by an integrated computational analysis and in vitro study. Predicted targets of CCA‑1.1 obtained using various databases were subjected to comprehensive downstream analyses, including functional annotation, disease and drug association analyses, protein–protein interaction network analyses, analyses of genetic alterations, expression,
and associations with survival and immune cell infiltration. Our integrative bioinformatics analysis revealed four candidate targets of CCA‑1.1 in GBM: TP53, EGFR, AKT1, and CASP3. In addition to targeting specific proteins with regulatory effects in GBM, CCA‑1.1 has the capacity to modulate the immunological milieu. Cytotoxicity of CCA‑1.1 was lower than TMZ with an IC50 value of 9.8 μM compared to TMZ with an IC50 of 40 μM. mRNA sequencing revealed EGFR transcript variant 8 was upregulated, whereas EGFRvIII was downregulated in U87 cells after treatment with CCA‑1.1. Furthermore, a molecular docking analysis suggested that CCA‑1.1 inhibits EGFR with various mutations in GBM, which was confirmed using molecular dynamics simulation, wherein the binding between CCA‑1.1 with the mutant EGFR L861Q was stable. For successful clinical translation, the effects of CCA‑1.1 need to be confirmed in laboratory studies and clinical trials. |
| first_indexed | 2024-03-14T00:02:05Z |
| format | Article |
| id | oai:generic.eprints.org:278771 |
| institution | Universiti Gadjah Mada |
| language | English |
| last_indexed | 2024-03-14T00:02:05Z |
| publishDate | 2022 |
| publisher | Springer |
| record_format | dspace |
| spelling | oai:generic.eprints.org:2787712023-11-02T00:34:04Z https://repository.ugm.ac.id/278771/ Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study Hermawan, Adam Wulandari, Febri Hanif, Naufa Utomo, Rohmad Yudi Jenie, Riris Istighfari Ikawati, Muthi' Tafrihani, Ahmad Syauqy Pharmaceutical Sciences The treatment of glioblastoma multiforme (GBM) is challenging owing to its localization in the brain, the limited capacity of brain cells to repair, resistance to conventional therapy, and its aggressiveness. Curcumin has anticancer activity against aggressive cancers, such as leukemia, and GBM; however, its application is limited by its low solubility and bioavailability. Chemoprevention curcumin analog 1.1 (CCA‑1.1), a curcumin analog, has better solubility and stability than those of curcumin. In this study, we explored potential targets of CCA‑1.1 in GBM (PTCGs) by an integrated computational analysis and in vitro study. Predicted targets of CCA‑1.1 obtained using various databases were subjected to comprehensive downstream analyses, including functional annotation, disease and drug association analyses, protein–protein interaction network analyses, analyses of genetic alterations, expression, and associations with survival and immune cell infiltration. Our integrative bioinformatics analysis revealed four candidate targets of CCA‑1.1 in GBM: TP53, EGFR, AKT1, and CASP3. In addition to targeting specific proteins with regulatory effects in GBM, CCA‑1.1 has the capacity to modulate the immunological milieu. Cytotoxicity of CCA‑1.1 was lower than TMZ with an IC50 value of 9.8 μM compared to TMZ with an IC50 of 40 μM. mRNA sequencing revealed EGFR transcript variant 8 was upregulated, whereas EGFRvIII was downregulated in U87 cells after treatment with CCA‑1.1. Furthermore, a molecular docking analysis suggested that CCA‑1.1 inhibits EGFR with various mutations in GBM, which was confirmed using molecular dynamics simulation, wherein the binding between CCA‑1.1 with the mutant EGFR L861Q was stable. For successful clinical translation, the effects of CCA‑1.1 need to be confirmed in laboratory studies and clinical trials. Springer 2022-08-17 Article PeerReviewed application/pdf en https://repository.ugm.ac.id/278771/1/Hermawan-3_FA.pdf Hermawan, Adam and Wulandari, Febri and Hanif, Naufa and Utomo, Rohmad Yudi and Jenie, Riris Istighfari and Ikawati, Muthi' and Tafrihani, Ahmad Syauqy (2022) Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study. Scientific Reports, 2022 (12). pp. 1-20. ISSN 2045-2322 https://www.nature.com/scientificreports https://doi.org/10.1038/s41598-022-18348-9 |
| spellingShingle | Pharmaceutical Sciences Hermawan, Adam Wulandari, Febri Hanif, Naufa Utomo, Rohmad Yudi Jenie, Riris Istighfari Ikawati, Muthi' Tafrihani, Ahmad Syauqy Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study |
| title | Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study |
| title_full | Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study |
| title_fullStr | Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study |
| title_full_unstemmed | Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study |
| title_short | Identification of potential targets of the curcumin analog CCA‑1.1 for glioblastoma treatment: integrated computational analysis and in vitro study |
| title_sort | identification of potential targets of the curcumin analog cca 1 1 for glioblastoma treatment integrated computational analysis and in vitro study |
| topic | Pharmaceutical Sciences |
| url | https://repository.ugm.ac.id/278771/1/Hermawan-3_FA.pdf |
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