Antitumorska aktivnost rutenijum(II) kompleksa na HCT 116 ćelije in vitro
Sažetak
Istraživanja su pokazala da kompleksi koji u svojoj strukturi sadrže rutenijum imaju snažan citotoksični efekat na različite cisplatin rezistentne malignitete. Takođe, Ru(II) I Ru(III) kompleksi su pokazali visok stepen selektivnosti prema maligno izmenjenim ćelijama, veoma slab efekat prema maligno neizmenjenim ćelijama, kao i antimetastatski efekat. Značajno je da rutenijum kompleksi imaju mogućnost vezivanja za DNK molekul tumorskih ćelija i na taj način smanjuju vijabilnost kancerskih ćelija. Pokazano je da se kompleksi rutenijuma mogu vezati za albumin i transferin čime se olakšava dopremanje ovih kompleksa do maligno izmenjenih ćelija. Stoga, cilj našeg istraživanja je ispitivanje biološkog efekta dva sintetisana Ru(II) kompleksa [Ru(Cl-Ph-tpy)(phen)Cl]Cl (K1) i [Ru(Cl-Ph-tpy)(o-bqdi)Cl]Cl (K2) na ćelije karcinoma kolona HCT 116, kao i definisanje mehanizma antitumorske aktivnosti kompleksa. Rezultati naše studije su nedvosmisleno pokazali da kompleksi rutenijuma obeleženi kao K1 i K2 imaju snažan citotoksični efekat na HCT116 tumorske ćelijske linije. Kompleks obeležen kao K1 je pokazao snažniji antitumorski efekat od K2 kompleksa i cisplatina. Takođe, kompleksi K1 I K2 su ispoljili citotoksični efekat na tumorske ćelijske linije indukcijom unutrašnjeg mitohondrijalnog puta.
Reference
1. Kryczka J, Kryczka J, Czarnecka-Chrebelska KH, Brzeziańska-Lasota E. Molecular Mechanisms of Chemoresistance Induced by Cisplatin in NSCLC Cancer Therapy. Int J Mol Sci. 2021;22(16):8885.
2. Makovec T. Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol Oncol. 2019;53(2):148-58.
3. Ghosh S. Cisplatin: The first metal based anticancer drug. Bioorg Chem. 2019;88:102925.
4. Sun Q, Li Y, Shi H, Wang Y, Zhang J, Zhang Q. Ruthenium Complexes as Promising Candidates against Lung Cancer. Molecules. 2021;26(15):4389.
5. Fabijańska M, Kasprzak MM, Ochocki J. Ruthenium(II) and Platinum(II) Complexes with Biologically Active Aminoflavone Ligands Exhibit In Vitro Anticancer Activity. Int J Mol Sci. 2021;22(14):7568.
6. Mohamed Subarkhan MK, Ren L, Xie B, Chen C, Wang Y, Wang H. Novel tetranuclear ruthenium(II) arene complexes showing potent cytotoxic and antimetastatic activity as well as low toxicity in vivo. Eur J Med Chem. 2019;179:246-56.
7. Čanović P, Simović AR, Radisavljević S, Bratsos I, Demitri N, Mitrović M, Zelen I, Bugarčić ŽD. Impact of aromaticity on anticancer activity of polypyridyl ruthenium(II) complexes: synthesis, structure, DNA/protein binding, lipophilicity and anticancer activity. J Biol Inorg Chem. 2017;22(7):1007-28.
8. Devi CS, Thulasiram B, Satyanarayana S, Nagababu P. Analytical Techniques Used to Detect DNA Binding Modes of Ruthenium(II) Complexes with Extended Phenanthroline Ring. J Fluoresc. 2017 Nov;27(6):2119-130.
9. de Melo ACC, Santana JMSVP, Nunes KJRC, Rodrigues BL, Castilho N, Gabriel P, Moraes AH, Marques MA, de Oliveira GAP, de Souza ÍP, Terenzi H, Pereira-Maia EC. New Heteroleptic Ruthenium(II) Complexes with Sulfamethoxypyridazine and Diimines as Potential Antitumor Agents. Molecules. 2019;24(11):2154.
10. Xu X, Lai Y, Hua ZC. Apoptosis and apoptotic body: disease message and therapeutic target potentials. Biosci Rep. 2019;39(1):BSR20180992.
11. Park SH, Shin I, Kim ND, Shin I. An Inhibitor of the Interaction of Survivin with Smac in Mitochondria Promotes Apoptosis. Chem Asian J. 2019 Nov 18;14(22):4035-41.
12. Rahmani M, Nkwocha J, Hawkins E, Pei X, Parker RE, Kmieciak M, Leverson JD, Sampath D, Ferreira-Gonzalez A, Grant S. Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells. Cancer Res. 2018;78(11):3075-86.
13. Chen T, Mei WJ, Wong YS, Liu J, Liu Y, Xie HS, Zheng WJ. Correction: Chiral ruthenium polypyridyl complexes as mitochondria-targeted apoptosis inducers. Medchemcomm. 2018;9(4):745.
14. Baliza IRS, Silva SLR, Santos LS, Neto JHA, Dias RB, Sales CBS, Rocha CAG, Soares MBP, Batista AA, Bezerra DP. Ruthenium Complexes With Piplartine Cause Apoptosis Through MAPK Signaling by a p53-Dependent Pathway in Human Colon Carcinoma Cells and Inhibit Tumor Development in a Xenograft Model. Front Oncol. 2019;9:582.
15. Lin K, Zhao ZZ, Bo HB, Hao XJ, Wang JQ. Applications of Ruthenium Complex in Tumor Diagnosis and Therapy. Front Pharmacol. 2018;9:1323.
16. Gałczyńska K, Drulis-Kawa Z, Arabski M. Antitumor Activity of Pt(II), Ru(III) and Cu(II) Complexes. Molecules. 2020;25(15):3492.
17. Gatti A, Habtemariam A, Romero-Canelón I, Song JI, Heer B, Clarkson GJ, Rogolino D, Sadler PJ, Carcelli M. Half-Sandwich Arene Ruthenium(II) and Osmium(II) Thiosemicarbazone Complexes: Solution Behavior and Antiproliferative Activity. Organometallics. 2018;37(6):891-99.
18. Savic M, Arsenijevic A, Milovanovic J, Stojanovic B, Stankovic V, Rilak Simovic A, Lazic D, Arsenijevic N, Milovanovic M. Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo. Molecules. 2020;25(20):4699.
19. Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol. 2020;21(4):204-24.
20. Popov LD. Mitochondrial biogenesis: An update. J Cell Mol Med. 2020;24(9):4892-99.
21. Singh A, Kukreti R, Saso L, Kukreti S. Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules. 2019;24(8):1583.
22. Riley JS, Tait SW. Mitochondrial DNA in inflammation and immunity. EMBO Rep. 2020;21(4):e49799.
23. Priesnitz C, Becker T. Pathways to balance mitochondrial translation and protein import. Genes Dev. 2018;32(19-20):1285-96.
24. Jiang M, Qi L, Li L, Li Y. The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer. Cell Death Discov. 2020;6:112.
25. Nagata S. Apoptosis and Clearance of Apoptotic Cells. Annu Rev Immunol. 2018 Apr 26;36:489-517.
26. Faria RS, Silva HD, Mello-Andrade F, Pires WC, de Castro Pereira F, de Lima AP, de Fátima Oliveira Santos S, Teixeira TM, da Silva PFF, Naves PLF, Batista AA, da Silva Oliveira RJ, Reis RM, de Paula Silveira-Lacerda E. Ruthenium(II)/Benzonitrile Complex Induces Cytotoxic Effect in Sarcoma-180 Cells by Caspase-Mediated and Tp53/p21-Mediated Apoptosis, with Moderate Brine Shrimp Toxicity. Biol Trace Elem Res. 2020;198(2):669-80.
27. Jiang GB, Xie YY, Lin GJ, Huang HL, Liang ZH, Liu YJ. Synthesis, characterization, DNA interaction, antioxidant and anticancer activity studies of ruthenium(II) polypyridyl complexes. J Photochem Photobiol B. 2013;129:48-56.