Anticancer activity of two ruthenium(II)-DMSO-chalcone complexes: Comparison of cytotoxic, pro-apoptotic and antimetastatic potential.
OBJECTIVE
Recently, we reported the synthesis and characterization of two complexes of general formula cis-[Ru(S-DMSO)3(R-CO-CH=CH-R')Cl] (R = 2-hydroxyphenyl for both, R' = thiophene (1), 3-methyl thiophene (2)) that showed remarkable topoisomerase II inhibition and strong binding with DNA. The aim of this study was the investigation of cytotoxic properties of these complexes against a panel of human tumor cell lines, with elucidation of their anticancer mechanisms in HeLa cells.


METHODS
Characterization of anticancer activity of the investigated ruthenium complexes 1 and 2 included analysis of cytotoxicity by MTT assay. Cell cycle phase disruption of HeLa cells treated with complexes 1 and 2 was analyzed by flow cytometry after propidium iodide (PI) staining. Annexin V-FITC/PI double staining and further flow cytometry analysis and acridine orange (AO)/ethidium bromide (EB) double staining and fluorescent microscopy were used to determine the apoptotic potential of the investigated ruthenium complexes. The inhibitory effect on gelatinases (MMP-2 and MMP-9) as an indication of possible antimetastatic potential was also analyzed using gelatine zymography.


RESULTS
The 50% cell growth inhibition (IC50) values of the investigated complexes ranged between 22.9 and 76.8 μM, with complex 2 being more cytotoxic. Both complexes induced G2 phase cell cycle arrest and apoptosis in HeLa cells. Inhibitory effect of complex 2 on MMP-2 activity was detected.


CONCLUSIONS
This work revealed the potential of the investigated Ru(II)-DMSO-chalcone complexes as anticancer agents with cytotoxic and pro-apoptotic activity and indicated complex 2 as leading compound for further chemical modifications and anticancer research.
Laboratory for Experimental Pharmacology, Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
Katarina K
KK
Jovanovic
Nevenka
N
Gligorijevic
Ruchi
R
Gaur
Lallan
L
Mishra
Sinisa
S
Radulovic
D017209:Apoptosis / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017975:Ruthenium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
D047188:Chalcones; D061965:Matrix Metalloproteinase Inhibitors; D017975:Ruthenium Compounds; D059005:Topoisomerase II Inhibitors; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D004121:Dimethyl Sulfoxide