Anticancer effects of ruthenium-sorafenib complexes in prostate cancer cell lines

Dilek Öztürk Civelek; Nida Ceren Çelik; Merve Çavuş; Belma Zengin Kurt

doi:10.47582/jompac.1869349

Anticancer effects of ruthenium-sorafenib complexes in prostate cancer cell lines

Abstract

Aims: To evaluate the cytotoxic and pro-apoptotic activities of newly synthesized ruthenium–sorafenib complexes (Ru1S–Ru8S) in prostate cancer models and to identify a lead candidate for advanced/castration-resistant prostate cancer. Methods: Ru1S–Ru8S were synthesized as previously described. Cytotoxicity was assessed by MTT in PC3, DU145, LNCaP, and, CCD1079Sk cells after 24 and 48 h exposure to 0.2–100 µM compounds; IC₅₀ values were calculated versus untreated controls. Apoptosis was analyzed in PC3 cells by Annexin V/7-AAD staining and flow cytometry after treatment with Ru1S, Ru3S, Ru4S, or sorafenib at graded concentrations. Molecular modelling examined potential binding interactions of Ru1S. Results: The complexes displayed cell line- and time-dependent cytotoxicity. At 48 h, Ru1S and Ru4S were among the most active complexes in cancer cells. Ru4S achieved the highest potency in cancer cells but was associated with extensive cell death displaying features consistent with both apoptotic and non-apoptotic processes. Ru1S induced prominent late-stage apoptosis in PC3 cells (comparable to Ru3S) while maintaining substantially lower toxicity in CCD-1079Sk cells. Sorafenib, although highly potent, exhibited considerable toxicity toward CCD-1079Sk cells. Modelling supported an androgen receptor–independent effect for Ru1S. Conclusion: Ruthenium coordination modulates sorafenib-driven cell-death pathways and may improve in vitro selectivity profiles compared with sorafenib. Ru1S emerged as a lead candidate for further preclinical evaluation in castration-resistant prostate cancer, based on its pro-apoptotic activity in PC3 cells and comparatively lower cytotoxicity in CCD-1079Sk fibroblasts relative to sorafenib.

Keywords

Supporting Institution

The authors declare that there is no real, potential, or perceived conflict of interest for this article.

Project Number

TUBITAK 217S645

Ethical Statement

We, the authors declare that the ethics committee approval is not required for this study.

Thanks

This study was supported by TUBITAK 217S645. N.C.C. and M.C. were recipients of TUBITAK 2209.

References

Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
Shafi AA, Yen AE, Weigel NL. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther. 2013;140(3):223-238. doi:10.1016/j.pharmthera.2013.07.003
Freedland SJ, Davis M, Epstein AJ, Arondekar B, Ivanova JI. Real-world treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer (mCRPC) in the US Medicare population. Prostate Cancer Prostatic Dis. 2024;27(2):327-333. doi:10. 1038/s41391-023-00725-8
Raval AD, Zhang Y, Korn M, Constantinovici N, McKay RR. Real-world utilization patterns and survival in men with metastatic prostate cancer treated with radium-223 in the United States. Prostate Cancer Prostatic Dis. 2025;1-8. doi:10.1038/s41391-025-00969-6
Yamamoto Y, De Velasco MA, Kura Y, et al. Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient prostate cancer. J Transl Med. 2015;13(1):150. doi:10.1186/s12967-015-0509-x
Steinbild S, Mross K, Frost A, et al. A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. Br J Cancer. 2007;97(11):1480-1485. doi:10.1038/sj.bjc.6604064
Yan X, Zhou Y, Li H, Jiang G, Sun H. Metallomics and metalloproteomics. In: Reedijk J, Poeppelmeier KR, eds. Comprehensive Inorganic Chemistry III. 3rd ed. Elsevier; 2023:53-76. doi:10.1016/B978-0-12-823144-9.00060-1
Heffeter P, Atil B, Kryeziu K, et al. The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo. Eur J Cancer. 2013;49(15):3366-3375. doi:10.1016/j.ejca.2013.05.018

Zengin Kurt B, Öztürk Civelek D, Çakmak EB, et al. Synthesis of sorafenib–ruthenium complexes, investigation of biological activities and applications in drug delivery systems as an anticancer agent. J Med Chem. 2024;67(6):4463-4482. doi:10.1021/acs.jmedchem.3c01115
Elsayed SA, Harrypersad S, Sahyon HA, El-Magd MA, Walsby CJ. Ruthenium(II)/(III) DMSO-based complexes of 2-aminophenyl benzimidazole with in vitro and in vivo anticancer activity. Molecules. 2020;25(18):Article 18. doi:10.3390/molecules25184284
Irace C, Misso G, Capuozzo A, et al. Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action. Sci Rep. 2017; 7(1):45236. doi:10.1038/srep45236
Pettinari R, Pettinari C, Marchetti F, et al. Arene-ruthenium(II) acylpyrazolonato complexes: apoptosis-promoting effects on human cancer cells. J Med Chem. 2014;57(11):4532-4542. doi:10.1021/jm500458c
Zhao Z, Gao P, You Y, Chen T. Cancer-targeting functionalization of selenium-containing ruthenium conjugate with tumor microenvironment- responsive property to enhance theranostic effects. Chem Eur J. 2018; 24(13):3289-3298. doi:10.1002/chem.201705561
Gaiddon C, Jeannequin P, Bischoff P, Pfeffer M, Sirlin C, Loeffler JP. Ruthenium(II)-derived organometallic compounds induce cytostatic and cytotoxic effects on mammalian cancer cell lines through p53-dependent and p53-independent mechanisms. J Pharmacol Exp Ther. 2005;315(3):1403-1411. doi:10.1124/jpet.105.089342
Sharma G, Rana NK, Singh P, Dubey P, Pandey DS, Koch B. P53-dependent apoptosis and cell cycle delay induced by heteroleptic complexes in human cervical cancer cells. Biomed Pharmacother. 2017; 88:218-231. doi:10.1016/j.biopha.2017.01.044
Neves SP, de Carvalho NC, da Silva MM, et al. Ruthenium complexes containing heterocyclic thioamidates trigger caspase-mediated apoptosis through MAPK signaling in human hepatocellular carcinoma cells. Front Oncol. 2019;9:562. doi:10.3389/fonc.2019.00562
de Carvalho NC, Neves SP, Dias RB, et al. A novel ruthenium complex with xanthoxylin induces S-phase arrest and causes ERK1/2-mediated apoptosis in HepG2 cells through a p53-independent pathway. Cell Death Dis. 2018;9(2):1-24. doi:10.1038/s41419-017-0104-6
Tan C, Lai S, Wu S, et al. Nuclear permeable ruthenium(II) β-carboline complexes induce autophagy to antagonize mitochondrial-mediated apoptosis. J Med Chem. 2010;53(21):7613-7624. doi:10.1021/jm1009296
Berndsen RH, Weiss A, Abdul UK, et al. Combination of ruthenium(II)-arene complex [Ru(η6-p-cymene)Cl2(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity. Sci Rep. 2017;7:43005. doi:10.1038/srep43005
Lai Y, Lu N, Luo S, Wang H, Zhang P. A photoactivated sorafenib-ruthenium(II) prodrug for resistant hepatocellular carcinoma therapy through ferroptosis and purine metabolism disruption. J Med Chem. 2022;65(19):13041-13051. doi:10.1021/acs.jmedchem.2c00880
Khan TA, Bhar K, Samanta R, et al. A bis-quinoline ruthenium(II) arene complex with submicromolar cytotoxicity in castration-resistant prostate cancer cells. Chem Commun (Camb). 2024;60(12):1579-1582. doi:10.1039/d3cc05083a
Robles-Escajeda E, Martínez A, Varela-Ramirez A, Sánchez-Delgado RA, Aguilera RJ. Analysis of the cytotoxic effects of ruthenium-ketoconazole and ruthenium-clotrimazole complexes on cancer cells. Cell Biol Toxicol. 2013;29(6):431-443. doi:10.1007/s10565-013-9264-z

Details

Primary Language

English

Subjects

Basic Pharmacology

Journal Section

Research Article

Authors

Dilek Öztürk Civelek ^*
0000-0003-2485-891X
Türkiye

Nida Ceren Çelik
0009-0003-7207-8325
Türkiye

Merve Çavuş
0009-0008-0876-0967
Türkiye

Belma Zengin Kurt
0000-0002-4663-5402
Türkiye

Publication Date

March 27, 2026

Submission Date

January 22, 2026

Acceptance Date

February 27, 2026

Published in Issue

Year 2026 Volume: 7 Number: 2

DOI

https://doi.org/10.47582/jompac.1869349

IZ

https://izlik.org/JA26AL47CC

Cite

RIS / Bibtex

APA

Öztürk Civelek, D., Çelik, N. C., Çavuş, M., & Zengin Kurt, B. (2026). Anticancer effects of ruthenium-sorafenib complexes in prostate cancer cell lines. Journal of Medicine and Palliative Care, 7(2), 261-268. https://doi.org/10.47582/jompac.1869349

AMA

1.Öztürk Civelek D, Çelik NC, Çavuş M, Zengin Kurt B. Anticancer effects of ruthenium-sorafenib complexes in prostate cancer cell lines. J Med Palliat Care / JOMPAC / jompac. 2026;7(2):261-268. doi:10.47582/jompac.1869349

Chicago

Öztürk Civelek, Dilek, Nida Ceren Çelik, Merve Çavuş, and Belma Zengin Kurt. 2026. “Anticancer Effects of Ruthenium-Sorafenib Complexes in Prostate Cancer Cell Lines”. Journal of Medicine and Palliative Care 7 (2): 261-68. https://doi.org/10.47582/jompac.1869349.

EndNote

Öztürk Civelek D, Çelik NC, Çavuş M, Zengin Kurt B (March 1, 2026) Anticancer effects of ruthenium-sorafenib complexes in prostate cancer cell lines. Journal of Medicine and Palliative Care 7 2 261–268.

IEEE

[1]D. Öztürk Civelek, N. C. Çelik, M. Çavuş, and B. Zengin Kurt, “Anticancer effects of ruthenium-sorafenib complexes in prostate cancer cell lines”, J Med Palliat Care / JOMPAC / jompac, vol. 7, no. 2, pp. 261–268, Mar. 2026, doi: 10.47582/jompac.1869349.

ISNAD

Öztürk Civelek, Dilek - Çelik, Nida Ceren - Çavuş, Merve - Zengin Kurt, Belma. “Anticancer Effects of Ruthenium-Sorafenib Complexes in Prostate Cancer Cell Lines”. Journal of Medicine and Palliative Care 7/2 (March 1, 2026): 261-268. https://doi.org/10.47582/jompac.1869349.

JAMA

1.Öztürk Civelek D, Çelik NC, Çavuş M, Zengin Kurt B. Anticancer effects of ruthenium-sorafenib complexes in prostate cancer cell lines. J Med Palliat Care / JOMPAC / jompac. 2026;7:261–268.

MLA

Öztürk Civelek, Dilek, et al. “Anticancer Effects of Ruthenium-Sorafenib Complexes in Prostate Cancer Cell Lines”. Journal of Medicine and Palliative Care, vol. 7, no. 2, Mar. 2026, pp. 261-8, doi:10.47582/jompac.1869349.

Vancouver

1.Dilek Öztürk Civelek, Nida Ceren Çelik, Merve Çavuş, Belma Zengin Kurt. Anticancer effects of ruthenium-sorafenib complexes in prostate cancer cell lines. J Med Palliat Care / JOMPAC / jompac. 2026 Mar. 1;7(2):261-8. doi:10.47582/jompac.1869349