Antitumor activity of Ru(III) complexes carrying beta-diketonato ligands in vitro and in vivo.
OBJECTIVE
To investigate the antitumor activity of two newly synthesized ruthenium(III) [Ru(III)] compounds carrying bidentate ligands: (acac)-acetylacetonate, [Ru(acac)3), and (tfac)-trifluoroacetylacetonate [Ru(tfac)3].


METHODS
The activity of ruthenium(III) analogues was evaluated on HeLa, B16, and Femx cell lines for cytotoxicity in vitro using MTT assay, and inhibition on tumor invading ability in vitro using cell migration and invasion assays, whereas inhibition of tumor growth in vivo was estimated on advanced B16 murine melanoma model. Both compounds were also investigated in combinations with cisplatin, oxaliplatin, or poly ADP-ribose polymerase- 1 (PARP-1) inhibitor, in order to determine the pattern of mutual interactions.


RESULTS
Applied as single drugs, Ru(tfac)3 showed high cytotoxic activity against HeLa and Femx cell lines, while Ru(acac)3 did not reach the IC50 on any of the cell lines tested. In combinations, Ru(acac)3 with cisplatin gained synergistic interaction, antagonistic with oxaliplatin, and of different kind with (PARP-1) inhibitor in concentration-and cell line-dependent manner. Ru(acac)3 exhibited inhibition of HeLa cell migration and gelatinolytic activity of MMP-2 and MMP-9. Ru(tfac)3 complexes did not induce significant reduction of melanoma growth in vivo, whereas Ru(acac)3 did, but the latter failed to contribute in lifespan improvement.


CONCLUSIONS
The investigated ruthenium complexes showed different levels of antitumor activity in vitro and in vivo, implicating on different mechanisms of their action as well as diverse perspectives in cancer treatment.
Arandjelovic
S S
SS
Laboratory for Experimental Pharmacology, Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.
Bjelogrlic
K S
KS
Malesevic
N N
NN
Tesic
Lj Z
LjZ
Radulovic
S S
SS
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006885:Hydroxybutyrates / Q000737:chemistry*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010422:Pentanones / Q000737:chemistry*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; D009944:Organoplatinum Compounds; D010422:Pentanones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017975:Ruthenium Compounds; D000077150:Oxaliplatin; C049529:acetyl acetonate; D002945:Cisplatin