Synthesis, characterization, and antitumor evaluation of a kaempferol–cobalt(II) complex targeting TMPRSS2 gene in lung cancer cells
Authors/Creators
- 1. Department of Pharmacognosy and Medicinal Plants, College of Pharmacy, University of Basrah, Basrah, Iraq
- 2. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Basrah, Basrah, Iraq
Description
Background: Transmembrane serine protease 2 (TMPRSS2) has been distinguished as a tumor suppressor in lung adenocarcinoma, and its reduced expression has been associated with disease progression.
Aim: To estimate the effects of a kaempferol–metal complex on lung cancer cells and assess its influence on TMPRSS2 gene expression in comparison with standard kaempferol.
Materials and methods: A kaempferol–cobalt(II) complex was synthesized, and the cytotoxicity of the complex against A549 lung cancer cells was estimated using an MTT assay. The mRNA expression of the TMPRSS2 gene was assessed using quantitative real-time PCR analysis.
Results: A molecular docking study revealed that the kaempferol–cobalt(II) complex displays better binding affinity toward TMPRSS2 compared with free kaempferol and selective cytotoxicity, with an IC50 value of 58.21 µg/mL. Quantitative real-time PCR analysis revealed that treatment with the kaempferol–cobalt(II) complex significantly elevated TMPRSS2 gene expression (7.3-fold).
Conclusion: Cobalt(II) complexation may be considered a promising candidate for further anticancer investigation.
Files
PHAR_article_187913.pdf
Files
(969.5 kB)
| Name | Size | Download all |
|---|---|---|
|
md5:d87c98bbfdd43046600e0cabe4b36cbd
|
912.4 kB | Preview Download |
|
md5:3d4657c6a0ee0a50ec750726d6765b21
|
57.1 kB | Preview Download |
Additional details
References
- Adhikari S, Nath P, Das A, Datta A, Baildya N, Duttaroy AK, Pathak S (2024) Biomedicine & Pharmacotherapy 171: 116211. https://doi.org/10.1016/j.biopha.2024.116211
- Giunchi F, Massari F, Altimari A, Gruppioni E, Nobili E, Fiorentino M, Ardizzoni A (2020) Dual TMPRSS2:ERG Fusion in a Patient with Lung and Prostate Cancers. Diagnostics 10: 1109. https://doi.org/10.3390/diagnostics10121109
- Hammad A, Namani A, Elshaer M, Wang XJ, Tang X (2019) "NRF2 addiction" in lung cancer cells and its impact on cancer therapy. Cancer Letters 467: 40–49. https://doi.org/10.1016/j.canlet.2019.09.016
- Herrera TES, Tello IPS, Mustafa MA, Jamil NY, Alaraj M, Atiyah Altameem KK, Alasheqi MQ, Hamoody A-HM, Alkhafaji AT, Shakir MN, Alshahrani MY, Alawadi A (2025) Kaempferol: Unveiling its anti-inflammatory properties for therapeutic innovation. Cytokine 186: 156846. https://doi.org/10.1016/j.cyto.2024.156846
- Jayed GS, Al-Dallee ZT, Al-Saad HN (2025) Synthesis of Kaempferol-Cr (III) Complex and study its Effect on Bax and Bcl-2 Genes Expression in SW480 Cell Lines. Medical Forum Monthly 36: 10. https://doi.org/10.60110/medforum.361011
- Kaur S, Mendonca P, Soliman KFA (2024) The Anticancer Effects and Therapeutic Potential of Kaempferol in Triple-Negative Breast Cancer. Nutrients 16: 2392. https://doi.org/10.3390/nu16152392
- Khan H, Patel S, Majumdar A (2021) Role of NRF2 and Sirtuin activators in COVID-19. Clinical Immunology 233: 108879. https://doi.org/10.1016/j.clim.2021.108879
- Khater M, Ravishankar D, Greco F, Osborn HM (2019) Metal Complexes of Flavonoids: Their Synthesis, Characterization and Enhanced Antioxidant and Anticancer Activities. Future Medicinal Chemistry 11: 2845–2867. https://doi.org/10.4155/fmc-2019-0237
- Kong Q, Xiang Z, Wu Y, Gu Y, Guo J, Geng F (2020) Analysis of the susceptibility of lung cancer patients to SARS-CoV-2 infection. Molecular Cancer 19: 80. https://doi.org/10.1186/s12943-020-01209-2
- Kumar P, Kumar P, Jain NP (2024) Preparation, Characterization and Evaluation of Antioxidant Flavonosomes. Journal of Drug Delivery and Therapeutics 14: 114–120. https://doi.org/10.22270/jddt.v14i6.6626
- Li M, Liu Y, Li M, Shang Z, Liu M, Han D (2021) Measurement and Correlation of the Solubility of Kaempferol Monohydrate in Pure and Binary Solvents. Fluid Phase Equilibria 539: 113027. https://doi.org/10.1016/j.fluid.2021.113027
- Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, Hood L, Nelson PS (1999) Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Research 59: 4180–4184.
- Liu X, Liu B, Shang Y, Cao P, Hou J, Chen F, Zhang B, Fan Y, Tan K (2022) Decreased TMPRSS2 expression by SARS-CoV-2 predicts the poor prognosis of lung cancer patients through metabolic pathways and immune infiltration. Aging 14: 73–108. https://doi.org/10.18632/aging.203823
- Liu Z, Lu Q, Zhang Z, Feng Q, Wang X (2024) TMPRSS2 is a tumor suppressor and its downregulation promotes antitumor immunity and immunotherapy response in lung adenocarcinoma. Respiratory Research 25: 238. https://doi.org/10.1186/s12931-024-02870-7
- van de Loosdrecht AA, Beelen RHJ, Ossenkoppele GJ, Broekhoven MG, Langenhuijsen MMAC (1994) A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. Journal of Immunological Methods 174: 311–320. https://doi.org/10.1016/0022-1759(94)90034-5
- Mihajlović LE, Trif M, Živković MB (2025) Metal Complexes with Hydroxyflavones: A Study of Anticancer and Antimicrobial Activities. Inorganics 13: 250. https://doi.org/10.3390/inorganics13080250
- Mohammed Ali Mohsen E, Saeed AAM, Alawi Bin Yahia A-R (2024) Synthesis, characterization, and bioactivity evaluation of several divalent transition metal ion-bioflavonoid complexes. Results in Chemistry 7: 101535. https://doi.org/10.1016/j.rechem.2024.101535
- Mutlu Gençkal H, Erkisa M, Alper P, Sahin S, Ulukaya E, Ari F (2020) Mixed ligand complexes of Co(II), Ni(II) and Cu(II) with quercetin and diimine ligands: synthesis, characterization, anti-cancer and anti-oxidant activity. JBIC Journal of Biological Inorganic Chemistry 25: 161–177. https://doi.org/10.1007/s00775-019-01749-z
- Park J-E, Gallagher T (2017) Lipidation increases antiviral activities of coronavirus fusion-inhibiting peptides. Virology 511: 9–18. https://doi.org/10.1016/j.virol.2017.07.033
- Pyo Y, Kwon KH, Jung YJ (2024) Anticancer Potential of Flavonoids: Their Role in Cancer Prevention and Health Benefits. Foods 13: 2253. https://doi.org/10.3390/foods13142253
- Shi J, Zhang ZT (2019) Synthesis, Crystal Structure, and Biological Activity of Two Complexes based on 5-hydroxy-4'-methoxyisoflavone-3'-sulfonate. Russian Journal of Coordination Chemistry 45: 244–252. https://doi.org/10.1134/S1070328419030084
- Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA: A Cancer Journal for Clinicians 70: 7–30. https://doi.org/10.3322/caac.21590
- Syed S, Y J, Chhetri D, Lalhriatpuii D (2023) Kaempferol Metal Complexes: A Multifaceted Approach to Synthesis, Characterization and Biological Activities. UTTAR PRADESH JOURNAL OF ZOOLOGY 44: 19–35. https://doi.org/10.56557/upjoz/2023/v44i223713
- Tumilaar SG, Hardianto A, Dohi H, Kurnia D (2024) A Comprehensive Review of Free Radicals, Oxidative Stress, and Antioxidants: Overview, Clinical Applications, Global Perspectives, Future Directions, and Mechanisms of Antioxidant Activity of Flavonoid Compounds [Ahmed M (Ed.)]. Journal of Chemistry 2024: 1–21. https://doi.org/10.1155/2024/5594386
- Verza FlA, Da Silva GC, Nishimura FG (2025) The impact of oxidative stress and the NRF2-KEAP1-ARE signaling pathway on anticancer drug resistance. Oncology Research 33: 1819–1834. https://doi.org/10.32604/or.2025.065755
- Wang Q, Huang M, Huang Y, Zhang J-S, Zhou G-F, Zeng R-Q, Yang X-B (2014) Synthesis, characterization, DNA interaction, and antitumor activities of mixed-ligand metal complexes of kaempferol and 1,10-phenanthroline/2,2'-bipyridine. Medicinal Chemistry Research 23: 2659–2666. https://doi.org/10.1007/s00044-013-0863-2
- Wang R, Deng Z, Zhu Z, Wang J, Yang X, Xu M, Wang X, Tang Q, Zhou Q, Wan X, Wu W, Wang S (2023) Kaempferol promotes non-small cell lung cancer cell autophagy via restricting Met pathway. Phytomedicine 121: 155090. https://doi.org/10.1016/j.phymed.2023.155090
- Xiao X, Shan H, Niu Y, Wang P, Li D, Zhang Y, Wang J, Wu Y, Jiang H (2022) TMPRSS2 Serves as a Prognostic Biomarker and Correlated With Immune Infiltrates in Breast Invasive Cancer and Lung Adenocarcinoma. Frontiers in Molecular Biosciences 9: 647826. https://doi.org/10.3389/fmolb.2022.647826
- Yang H, Xu H, Lin X, Cai Z, Xia Y, Wang Y, Chen Z, Zhang K, Wu Y, Wang J, Awadasseid A, Zhang W (2024) Design, synthesis and biological evaluation of novel TMPRSS2-PROTACs with florosubstituted 4-guanidino-N-phenylbenzamide derivative ligands. Bioorganic & Medicinal Chemistry 116: 117982. https://doi.org/10.1016/j.bmc.2024.117982
- Zangade SB, Dhulshette BS, Patil PB (2024) Flavonoid-metal ion Complexes as Potent Anticancer Metallodrugs: A Comprehensive Review. Mini-Reviews in Medicinal Chemistry 24: 1046–1060. https://doi.org/10.2174/0113895575273658231012040250
- Zanoaga O, Braicu C, Jurj A, Rusu A, Buiga R, Berindan-Neagoe I (2019) Progress in Research on the Role of Flavonoids in Lung Cancer. International Journal of Molecular Sciences 20: 4291. https://doi.org/10.3390/ijms20174291