Cellular sensitivity to beta-diketonato complexes of ruthenium(III), chromium(III) and rhodium(III).
The aim of this study was to investigate cellular response to several ruthenium(III), chromium(III) and rhodium(III) compounds carrying bidentate beta-diketonato ligands: [(acac)--acetylacetonate ligand, (tfac)--trifluoroacetylacetonate ligand]. Cell sensitivity studies were performed on several cell lines (A2780, cisplatin-sensitive and -resistant U2-OS and U2-OS/Pt, HeLa, B16) using growth-inhibition assay. Effect of intracellular GSH depletion on cell sensitivity to the agents was analyzed in A2780 cells. Flow cytometry was used to assess apoptosis by Annexin-V-FITC/PI staining, and to analyze induction of caspase-3 activity. Possible DNA binding/damaging affinity was investigated, by inductively coupled mass spectrometry, and by 14C-thymidine / 3H-uridine incorporation assay. Cell sensitivity studies showed that the pattern of sensitivity to Ru(tfac)3 complex of the two cisplatin-sensitive/-resistant osteosarcoma cell lines, U2-OS and U2-OS/Pt, was similar to that of A2780 cells (72 h exposure), with the IC50 being around 40 microM. The growth-inhibitory effect of Ru(acac)3 ranged over 100 microM, while Cr(III) and Rh(III) complexes were completely devoid of antitumor action in vitro. Ru(tfac)3 exhibited strong potential for apoptosis induction on A2780 cells (up to 40%) and caused cell cycle arrest in the S phase as well as decrease of the percent of G1 and G2 cells. Ru(acac)3-induced apoptosis was slightly higher than 10%, whereas activation of caspase-3 in HeLa cells was moderate. DNA binding study revealed that only Cr(acac)3 was capable of binding DNA, while Cr(III) and Ru(III) compounds possess potential to inhibit DNA/RNA synthesis. In conclusion, only Ru(III) complexes showed potential for antitumor action.
Arandjelovic
S
S
Dept for Drug Development, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia & Montenegro.
Tesic
Z
Z
Perego
P
P
Gatti
L
L
Carenini
N
N
Zunino
F
F
Leone
R
R
Apostoli
P
P
Radulovic
S
S
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002857:Chromium / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D012238:Rhodium / Q000494:pharmacology*; D012428:Ruthenium / Q000494:pharmacology*
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D002857:Chromium; D012428:Ruthenium; D012238:Rhodium; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases