Novel dual responsive embelin functionalised ZnO nanomaterials amplify DNA damage and induce apoptosis via pERK1/2/p53 pathway in pancreatic ductal adenocarcinoma.
| Title: | Novel dual responsive embelin functionalised ZnO nanomaterials amplify DNA damage and induce apoptosis via pERK1/2/p53 pathway in pancreatic ductal adenocarcinoma. |
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| Authors: | Rajaput PS; Laboratory of Experimental Medicine, Department of PG Studies and Research in Biotechnology, Kuvempu University, Shankarghatta 577451, Karnataka, India.; Hari Krishna R; Department of Chemistry, M. S. Ramaiah Institute of Technology, Bangalore 560054, India.; Pradeepa K; Department of Biotechnology, Sahyadri Science College, Kuvempu University, Vidya Nagara, Shivamogga, Karnataka 577203, India.; Meghana P; Laboratory of Experimental Medicine, Department of PG Studies and Research in Biotechnology, Kuvempu University, Shankarghatta 577451, Karnataka, India.; Sandeep Kumar Jain R; Laboratory of Experimental Medicine, Department of PG Studies and Research in Biotechnology, Kuvempu University, Shankarghatta 577451, Karnataka, India.; Prashanth N; Laboratory of Experimental Medicine, Department of PG Studies and Research in Biotechnology, Kuvempu University, Shankarghatta 577451, Karnataka, India.; Ravindranath BS; Department of Biotechnology, Manipal Institute of technology, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India.; Sharath R; Department of Food technology, Davanagere University, Shivagangotri, Davanagere, Karnataka 577007, India.; Satyanarayan ND; Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur, Chikkamagaluru 577548, Karnataka, India.; Raja Naika H; Department of Environmental Science, Central University of Kerala, Tejaswini Hills, Periya, Kasaragod 671320, Kerala, India.; Kumaraswamy HM; Laboratory of Experimental Medicine, Department of PG Studies and Research in Biotechnology, Kuvempu University, Shankarghatta 577451, Karnataka, India. Electronic address: drhmklab@gmail.com. |
| Source: | Biomaterials advances [Biomater Adv] 2026 Feb; Vol. 179, pp. 214470. Date of Electronic Publication: 2025 Aug 23. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 9918383886206676 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2772-9508 (Electronic) Linking ISSN: 27729508 NLM ISO Abbreviation: Biomater Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Amsterdam] : Elsevier B.V., [2022]- |
| MeSH Terms: | Zinc Oxide*/chemistry ; Zinc Oxide*/pharmacology ; Apoptosis*/drug effects ; Benzoquinones*/chemistry ; Benzoquinones*/pharmacology ; Carcinoma, Pancreatic Ductal*/pathology ; Carcinoma, Pancreatic Ductal*/drug therapy ; Carcinoma, Pancreatic Ductal*/metabolism ; DNA Damage*/drug effects ; Pancreatic Neoplasms*/drug therapy ; Pancreatic Neoplasms*/pathology ; Pancreatic Neoplasms*/metabolism ; MAP Kinase Signaling System*/drug effects ; Nanostructures*/chemistry; Tumor Suppressor Protein p53/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Humans ; Cell Line, Tumor |
| Abstract: | Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemoresistance. Nano-bioconjugates, due to their enhanced surface-to-volume ratio, offer significant potential in cancer therapy. In this study, we synthesized ZnO nanoparticles (NPs) using solution combustion method and exhibited a particle size range of 20-70 nm as confirmed by TEM analysis. These NPs were conjugated with embelin, a natural benzoquinone compound. Successful conjugation was confirmed using FTIR spectroscopy. Structural and morphological characteristics of the conjugates were confirmed using XRD, SEM, TEM, FTIR, and EDS color mapping. Embelin conjugated ZnO NPs (Emb-ZnO NPs) were evaluated against PDAC cell lines (PANC-1 and MIA PaCa-2). The nanoconjugates showed significant cytotoxicity compared to individual Embelin and ZnO NPs, with IC50 values of 7.05 ± 0.96 μg/ml (PANC-1) and 8.66 ± 1.46 μg/ml (MIA PaCa-2). Emb-ZnO NPs exhibited tumoricidal effects in clonogenic and migration assays. Fluorescent staining revealed disrupted cellular architecture and significant apoptosis. Immunoblot analysis exhibits deregulation of key pathways, including amplified expression of γ-H2AX (88.48 %), indicative of DNA damage. Concurrently, elevated levels of pChk2 (68.07 %), p53 (89.34 %), and caspase-3 (26.67 %) promote Cell cycle halting and programmed cell death triggered by genomic instability. Conversely, reduced pERK1/2 (53.77 %) expression suggested inhibition of the MAPK pathway by Emb-ZnO NPs. Additionally, the formulation inhibited neovascularization in the CAM model, indicating anti-angiogenic potential. Molecular dynamics simulations of p53 and pERK1/2 aligned with in vitro results. In conclusion, Emb-ZnO NPs is a promising therapeutic candidate for PDAC and other cancers.; (Copyright © 2025 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kumaraswamy H M reports equipment, drugs, or supplies was provided by Vision Group on Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: DNA damage response pathway; Drug discovery; Embelin; Functional nanomaterials; Nanobioconjugates; Pancreatic cancer; ZnO nanoparticles |
| Substance Nomenclature: | SOI2LOH54Z (Zinc Oxide); 0 (Benzoquinones); 0 (Tumor Suppressor Protein p53); SHC6U8F5ER (embelin); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); 0 (Antineoplastic Agents) |
| Entry Date(s): | Date Created: 20250906 Date Completed: 20251011 Latest Revision: 20251011 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.bioadv.2025.214470 |
| PMID: | 40913851 |
| Database: | MEDLINE |
Journal Article