Ruthenium-enhanced curcumin derivatives target tumor growth and cancer-related inflammation in head and neck cancer models

. 2025 ; 15 () : 1708944. [epub] 20251217

Status PubMed-not-MEDLINE Jazyk angličtina Země Švýcarsko Médium electronic-ecollection

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/pmid41479792

INTRODUCTION: Head and neck cancers (HNC) remain a significant clinical challenge, particularly due to their association with chronic inflammation triggered by tobacco carcinogens and human papillomavirus (HPV) infection. Persistent activation of proinflammatory and proangiogenic pathways, including nuclear factor kappa B (NF-kB), interleukin 6 (IL-6), and interleukin 8 (IL-8), plays a crucial role in tumor progression. METHODS: In this study, we synthetized ruthenium-enhanced curcumin derivatives (complexes 3 and 4) and study their anti-inflammatory and anticancer properties by using HNC cell lines. RESULTS: Complex 3 demonstrated potent cytotoxic and antiproliferative effects across both HPV-negative and HPV- positive HNC cell lines, while complex 4 showed selectivity toward oral squamous cell carcinoma (OSCC). Both complexes exhibited cytostatic and migrastatic activities. Importantly, treatment with these complexes significantly suppressed NF-kB activity and reduced IL-6 and IL-8 levels more effectively than native curcumin. DISCUSSION: These findings highlight their potential not only as stand-alone therapeutic agents but also as adjuvants in combination therapies for HNC.

Zobrazit více v PubMed

Barsouk A, Aluru JS, Rawla P, Saginala K, Barsouk A. Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma. Med Sci. (2023) 11:42. doi:  10.3390/medsci11020042, PMID: PubMed DOI PMC

Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. (2020) 6:92. doi:  10.1038/s41572-020-00224-3, PMID: PubMed DOI PMC

Veselá K, Kejík Z, Masařík M, Babula P, Dytrych P, Martásek P, et al. Curcumin: A potential weapon in the prevention and treatment of head and neck cancer. ACS Pharmacol Transl Sci. (2024) 7:3394–418. doi:  10.1021/acsptsci.4c00518, PMID: PubMed DOI PMC

Thakral A, Lee JJW, Hou T, Hueniken K, Dudding T, Gormley M, et al. Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study. Nat Commun. (2024) 15:7835. doi:  10.1038/s41467-024-51679-x, PMID: PubMed DOI PMC

Baez A. Genetic and Environmental Factors in Head and Neck Cancer Genesis. Journal of environmental science and health Part C. Environ carcinogenesis ecotoxicology Rev. (2008) 26:174–200. doi:  10.1080/10590500802129431, PMID: PubMed DOI

Anto R, Mukhopadhyay A, Shishodia S, Gairola C, Aggarwal B. Cigarette smoke condensate activates nuclear transcription factor-κB through phosphorylation and degradation of IκBα: Correlation with induction of cyclooxygenase-2. Carcinogenesis. (2002) 23:1511–8. doi:  10.1093/carcin/23.9.1511, PMID: PubMed DOI

Thapa R, Moglad E, Goyal A, Bhat AA, Almalki WH, Kazmi I, et al. Deciphering NF-kappaB pathways in smoking-related lung carcinogenesis. Excli J. (2024) 23:991–1017. doi:  10.17179/excli2024-7475, PMID: PubMed DOI PMC

Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduction Targeted Ther. (2020) 5:209. doi:  10.1038/s41392-020-00312-6, PMID: PubMed DOI PMC

Li Y, Yadollahi P, Essien FN, Putluri V, Ambati CSR, Kami Reddy KR, et al. Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer. J Trans Med. (2025) 23:403. doi:  10.1186/s12967-025-06258-z, PMID: PubMed DOI PMC

Li K, Zeng X, Liu P, Zeng X, Lv J, Qiu S, et al. The role of inflammation-associated factors in head and neck squamous cell carcinoma. J Inflammation Res. (2023) 16:4301–15. doi:  10.2147/JIR.S428358, PMID: PubMed DOI PMC

Strzelak A, Ratajczak A, Adamiec A, Feleszko W. Tobacco smoke induces and alters immune responses in the lung triggering inflammation, allergy, asthma and other lung diseases: A mechanistic review. Int J Environ Res Public Health. (2018) 15:1033. doi:  10.3390/ijerph15051033, PMID: PubMed DOI PMC

Musella G, Coppini M, França Vieira E Silva F, Campisi G, Pérez-Sayáns M, Caponio VCA, et al. Tumor–stroma ratio in head and neck squamous cell carcinoma: A systematic review and meta-analysis. Oral Dis. 31(8):2382–93. doi:  10.1111/odi.15319, PMID: PubMed DOI PMC

Hong Y, Liu Y, Shen H, Li B, Li Q. A strategy for synergistic enhancement of immune circulation in head and neck squamous cell carcinoma by novel nucleic acid drug therapy and immunotherapy. J Transl Med. (2025) 23:354. doi:  10.1186/s12967-025-06344-2, PMID: PubMed DOI PMC

Prasad S, DuBourdieu D, Srivastava A, Kumar P, Lall R. Metal–curcumin complexes in therapeutics: an approach to enhance pharmacological effects of curcumin. Int J Mol Sci. (2021) 22:7094. doi:  10.3390/ijms22137094, PMID: PubMed DOI PMC

Shi C, Yuan Z, Liu T, Chan L, Chen T, Zhao J. X-ray sensitive selenium-containing Ru complexes sensitize nasopharyngeal carcinoma cells for radio/chemotherapy. J Materials Chem B. (2023) 11:5607–18. doi:  10.1039/D3TB00064H, PMID: PubMed DOI

Zeng L, Gupta P, Chen Y, Wang E, Ji L, Chao H, et al. The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials. Chem Soc Rev. (2017) 46:5771–804. doi:  10.1039/C7CS00195A, PMID: PubMed DOI PMC

Santi M, Mapanao AK, Biancalana L, Marchetti F, Voliani V. Ruthenium arene complexes in the treatment of 3D models of head and neck squamous cell carcinomas. Eur J Medicinal Chem. (2021) 212:113143. doi:  10.1016/j.ejmech.2020.113143, PMID: PubMed DOI

Garufi A, Baldari S, Pettinari R, Gilardini Montani MS, D’Orazi V, Pistritto G, et al. A ruthenium(II)-curcumin compound modulates NRF2 expression balancing the cancer cell death/survival outcome according to p53 status. J Exp Clin Cancer Res. (2020) 39:122. doi:  10.1186/s13046-020-01628-5, PMID: PubMed DOI PMC

Dytrych P, Kejík Z, Hajduch J, Kaplánek R, Veselá K, Kučnirová K, et al. Therapeutic potential and limitations of curcumin as antimetastatic agent. BioMed Pharmacother. (2023) 163:114758. doi:  10.1016/j.biopha.2023.114758, PMID: PubMed DOI

Chow MJ, Babak MV, Wong DYQ, Pastorin G, Gaiddon C, Ang WH. Structural determinants of p53-independence in anticancer ruthenium-arene schiff-base complexes. Mol Pharmaceutics. (2016) 13:2543–54. doi:  10.1021/acs.molpharmaceut.6b00348, PMID: PubMed DOI

Dash P, Nayak S, Parida PK. The efficacy of curcumin in reducing immunosuppressive states of peripheral blood mononuclear cells extracted from oral squamous cell carcinoma patients: an PubMed DOI PMC

LoTempio MM, Veena MS, Steele HL, Ramamurthy B, Ramalingam TS, Cohen AN, et al. Curcumin suppresses growth of head and neck squamous cell carcinoma. Clin Cancer Res. (2005) 11:6994–7002. doi:  10.1158/1078-0432.CCR-05-0301, PMID: PubMed DOI

Allen CT, Ricker JL, Chen Z, Van Waes C. Role of activated nuclear factor-kappaB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck. Head Neck. (2007) 29:959–71. doi:  10.1002/hed.20615, PMID: PubMed DOI

Chung CH, Parker JS, Ely K, Carter J, Yi Y, Murphy BA, et al. Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-kappaB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res. (2006) 66:8210–8. doi:  10.1158/0008-5472.CAN-06-1213, PMID: PubMed DOI

Barnes P, Mensah A, Derkyi-Kwarteng L, Adankwa E, Agbo E, Yahaya ES, et al. NF−κB (p65) protein expression in head and neck tumors and its association with clinicopathological parameters. World Acad Sci J. (2025) 7:42. doi:  10.3892/wasj.2025.330 DOI

Marret G, Temam S, Kamal M, Even C, Delord J-P, Hoffmann C, et al. Randomized phase II study of preoperative afatinib in untreated head and neck cancers: predictive and pharmacodynamic biomarkers of activity. Sci Rep. (2023) 13:22524. doi:  10.1038/s41598-023-49887-4, PMID: PubMed DOI PMC

Wang D, Veena MS, Stevenson K, Tang C, Ho B, Suh JD, et al. Liposome-encapsulated curcumin suppresses growth of head and neck squamous cell carcinoma PubMed DOI

Mohankumar K, Francis AP, Pajaniradje S, Rajagopalan R. Synthetic curcumin analog: inhibiting the invasion, angiogenesis, and metastasis in human laryngeal carcinoma cells via NF-kB pathway. Mol Biol Rep. (2021) 48:6065–74. doi:  10.1007/s11033-021-06610-8, PMID: PubMed DOI

Niklander SE. Inflammatory mediators in oral cancer: pathogenic mechanisms and diagnostic potential. Front Oral Health. (2021) 2. doi:  10.3389/froh.2021.642238, PMID: PubMed DOI PMC

Arora D, Ganapathy DM, Usman Pp AS, Ameya KP, Sekar D, Kaliaperumal K. Expression analysis of nuclear factor kappa B (NF-κB) in oral squamous cell carcinoma. Oral Oncol Rep. (2024) 10:100481. doi:  10.1016/j.oor.2024.100481 DOI

Arthur AE, Peterson KE, Shen J, Djuric Z, Taylor JM, Hebert JR, et al. Diet and proinflammatory cytokine levels in head and neck squamous cell carcinoma. Cancer. (2014) 120:2704–12. doi:  10.1002/cncr.28778, PMID: PubMed DOI PMC

Russo N, Bellile E, Murdoch-Kinch CA, Liu M, Eisbruch A, Wolf GT, et al. Cytokines in saliva increase in head and neck cancer patients after treatment. Oral Surg Oral Med Oral Pathol Oral Radiol. (2016) 122:483–90.e1. doi:  10.1016/j.oooo.2016.05.020, PMID: PubMed DOI PMC

Li S, Xu G, Zhu Y, Zhao J, Gou S. Bifunctional ruthenium(ii) polypyridyl complexes of curcumin as potential anticancer agents. Dalton Trans. (2020) 49:9454–63. doi:  10.1039/D0DT01040E, PMID: PubMed DOI

Caruso F, Pettinari R, Rossi M, Monti E, Gariboldi MB, Marchetti F, et al. The PubMed DOI

Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The protein data bank. Nucleic Acids Res. (2000) 28:235–42. doi:  10.1093/nar/28.1.235, PMID: PubMed DOI PMC

Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of coot. Acta Crystallogr D Biol Crystallogr. (2010) 66:486–501. doi:  10.1107/S0907444910007493, PMID: PubMed DOI PMC

Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock vina 1.2.0: new docking methods, expanded force field, and python bindings. J Chem Inf Modeling. (2021) 61:3891–8. doi:  10.1021/acs.jcim.1c00203, PMID: PubMed DOI PMC

Meng EC, Goddard TD, Pettersen EF, Couch GS, Pearson ZJ, Morris JH, et al. UCSF ChimeraX: Tools for structure building and analysis. Protein Science. (2023) 32:e4792. doi:  10.1002/pro.4792, PMID: PubMed DOI PMC

Krieger E JK, Lee J, Lee J, Raman S, Thompson J, Tyka M, et al. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8. Proteins. (2009) 77 Suppl 9:114–22. doi:  10.1002/prot.22570, PMID: PubMed DOI PMC

Schrödinger LLC. ed. The pyMOL Molecular Graphics System, Version 3.0.

Systèmes D. BIOVIA Workbook. (2024), BIOVIA, Dassault Systèmes.

Deng Y, Zhang Q, Qu D-H. Emerging hydrogen-bond design for high-performance dynamic polymeric materials. ACS Materials Letters. (2023) 5:480–90. doi:  10.1021/acsmaterialslett.2c00865 DOI

Veselá K, Kejík Z, Abramenko N, Kaplánek R, Jakubek M, Petrlova J. Investigating antibacterial and anti-inflammatory properties of synthetic curcuminoids. Front Med. (2024) 11. doi:  10.3389/fmed.2024.1478122, PMID: PubMed DOI PMC

Moorthy H, Yadav M, Tamang N, Mavileti SK, Singla L, Choudhury AR, et al. Antiplasmodial and Antimalarial Activity of 3,5-Diarylidenetetrahydro-2H-pyran-4(3H)-ones via Inhibition of Plasmodium falciparum Pyridoxal Synthase. ChemMedChem. (2023) 18:e202200411. doi:  10.1002/cmdc.202200411, PMID: PubMed DOI

Wang L, Sheng J, Wu W, Han J, Fan Z, Qian C. A convenient synthesis of α,α′Bis(substituted benzylidene)cycloalkanones catalyzed by yb(OTf) 3 under solvent-free conditions. Synthesis-stuttgart. (2004) 36:3060–4. doi:  10.1055/s-2004-834900 DOI

Ba P, Xu M, Yu M, Li L, Duan X, Lv S, et al. Curcumin suppresses the proliferation and tumorigenicity of Cal27 by modulating cancer-associated fibroblasts of TSCC. Oral Diseases. (2020) 26:1375–83. doi:  10.1111/odi.13306, PMID: PubMed DOI

Ma C, Zhuang Z, Su Q, He J-F, Li H. Curcumin Has Anti-Proliferative and Pro-Apoptotic Effects on Tongue Cancer PubMed DOI PMC

Borges G, Elias S, Amorim B, de Lima C, Coletta R, Castilho R, et al. Curcumin downregulates the PI3K–AKT–mTOR pathway and inhibits growth and progression in head and neck cancer cells. Phytotherapy Res. (2020) 34:3311–24. doi:  10.1002/ptr.6780, PMID: PubMed DOI

Xiao C, Wang L, Zhu L, Zhang C, Zhou J. Curcumin inhibits oral squamous cell carcinoma SCC-9 cells proliferation by regulating miR-9 expression. Biochem Biophys Res Commun. (2014) 454:576–80. doi:  10.1016/j.bbrc.2014.10.122, PMID: PubMed DOI

Mojzeš A, Tomljanović M, Milković L, Kujundžić RN, Gašparović A, Trošelj KG. Cell-type specific metabolic response of cancer cells to curcumin. Int J Mol Sci. (2020) 21:1661. doi:  10.3390/ijms21051661, PMID: PubMed DOI PMC

Lin Y-T, Wang L-F, Hsu Y-C. Curcuminoids suppress the growth of pharynx and nasopharyngeal carcinoma cells through induced apoptosis. J Agric Food Chem. (2009) 57:3765–70. doi:  10.1021/jf803758x, PMID: PubMed DOI

Kumaravel M, Sankar P, Latha P, Benson CS, Rukkumani R. Antiproliferative effects of an analog of curcumin in Hep-2 cells: a comparative study with curcumin. Nat Prod Commun. (2013) 8:183–6. doi:  10.1177/1934578X1300800213, PMID: PubMed DOI

Kumbar VM, Muddapur U, Bin Muhsinah A, Alshehri SA, Alshahrani MM, Almazni IA, et al. Curcumin-encapsulated nanomicelles improve cellular uptake and cytotoxicity in cisplatin-resistant human oral cancer cells. J Funct Biomater. (2022) 13(4):158. doi:  10.3390/jfb13040158, PMID: PubMed DOI PMC

Rujirachotiwat A, Suttamanatwong S. Curcumin upregulates transforming growth factor-β1, its receptors, and vascular endothelial growth factor expressions in an PubMed DOI PMC

Xi Y, Gao H, Callaghan MU, Fribley AM, Garshott DM, Xu ZX, et al. Induction of BCL2-interacting killer, BIK, is mediated for anti-cancer activity of curcumin in human head and neck squamous cell carcinoma cells. J Cancer. (2015) 6:327–32. doi:  10.7150/jca.11185, PMID: PubMed DOI PMC

Chen J, Zhang L, Shu Y, Chen L, Zhu M, Yao S, et al. Curcumin analogue CA15 exhibits anticancer effects on HEp-2 cells via targeting NF-κB. BioMed Res Int. (2017) 2017:4751260. doi:  10.1155/2017/3236424, PMID: PubMed DOI PMC

Ohnishi Y, Sakamoto T, Zhengguang L, Yasui H, Hamada H, Kubo H, et al. Curcumin inhibits epithelial-mesenchymal transition in oral cancer cells via c-Met blockade. Oncol Lett. (2020) 19:4177–82. doi:  10.3892/ol.2020.11523, PMID: PubMed DOI PMC

Ardito F, Perrone D, Giuliani M, Testa NF, Muzio LL. Effects of curcumin on squamous cell carcinoma of tongue: an PubMed DOI

Meyer C, Pries R, Wollenberg B. Established and novel NF-κB inhibitors lead to downregulation of TLR3 and the proliferation and cytokine secretion in HNSCC. Oral Oncol. (2011) 47:818–26. doi:  10.1016/j.oraloncology.2011.06.010, PMID: PubMed DOI

Vander Broek R, Snow GE, Chen Z, Van Waes C. Chemoprevention of head and neck squamous cell carcinoma through inhibition of NF-κB signaling. Oral Oncol. (2014) 50:930–41. doi:  10.1016/j.oraloncology.2013.10.005, PMID: PubMed DOI PMC

Wang F, Arun P, Friedman J, Chen Z, Van Waes C. Current and potential inflammation targeted therapies in head and neck cancer. Curr Opin Pharmacol. (2009) 9:389–95. doi:  10.1016/j.coph.2009.06.005, PMID: PubMed DOI PMC

Cohen AN, Veena MS, Srivatsan ES, Wang MB. Suppression of interleukin 6 and 8 production in head and neck cancer cells with curcumin via inhibition of Iκβ Kinase. Arch Otolaryngology–Head Neck Surgery. (2009) 135:190–7. doi:  10.1001/archotol.135.2.190, PMID: PubMed DOI

Villegas C, González-Chavarría I, Burgos V, Cabrera-Pardo JR, Schmidt B, Paz C. Erioflorin and erioflorin acetate induce cell death in advanced prostate cancer through ROS increase and NF-κB inhibition. J Xenobiotics. (2025) 15:45. doi:  10.3390/jox15020045, PMID: PubMed DOI PMC

Shukla NM, Chan M, Lao FS, Chu PJ, Belsuzarri M, Yao S, et al. Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation. Bioorganic Medicinal Chem. (2021) 43:116242. doi:  10.1016/j.bmc.2021.116242, PMID: PubMed DOI PMC

Dan H, Liu S, Liu J, Liu D, Yin F, Wei Z, et al. RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF-κB pathway in oral squamous cell carcinoma. Mol Oncol. (2020) 14:795–807. doi:  10.1002/1878-0261.12644, PMID: PubMed DOI PMC

Liu C, Wu K, Li C, Zhang Z, Zhai P, Guo H, et al. SPP1+ macrophages promote head and neck squamous cell carcinoma progression by secreting TNF-α and IL-1β. J Exp Clin Cancer Res. (2024) 43:332. doi:  10.1186/s13046-024-03255-w, PMID: PubMed DOI PMC

Wei D, Liu J, Ma J. The value of lymphocyte to monocyte ratio in the prognosis of head and neck squamous cell carcinoma: a meta-analysis. PeerJ. (2023) 11:e16014. doi:  10.7717/peerj.16014, PMID: PubMed DOI PMC

Heimdal JH, Kross K, Klementsen B, Olofsson J, Aarstad HJ. Stimulated monocyte IL-6 secretion predicts survival of patients with head and neck squamous cell carcinoma. BMC Cancer. (2008) 8:34. doi:  10.1186/1471-2407-8-34, PMID: PubMed DOI PMC

Marei HE, Althani A, Afifi N, Hasan A, Caceci T, Pozzoli G, et al. p53 signaling in cancer progression and therapy. Cancer Cell Int. (2021) 21:703. doi:  10.1186/s12935-021-02396-8, PMID: PubMed DOI PMC

Najít záznam

Citační ukazatele

Pouze přihlášení uživatelé

Možnosti archivace

Nahrávání dat ...