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.

The evaluation of cytotoxic activity of planar pentadentate ligand 2',2"'-(2,6-pyridindiyldiethylidyne) dioxamohydrazide dihydrate (H2l x 2H2O) and its metal coordination complexes; pitfalls in the use of the MTT-assay.

In this study we have investigated, for the first time to our knowledge, the antineoplastic activity of a planar pentadentate ligand (H2L.2H2O = 2', 2'''-(2,6-pyridindiyldiethylidyne)dioxamohydrazide dihydrate) and some of its metal coordination complexes [Cu(L)(H2O)].H2O, [Cu(HL)(H2O)]Cl04, [Co(L)(H20)2] 6H20, [Co(H2L)(H2O)(MeOH)](ClO4)2 and [Fe(L)(H2O)2]ClO4-3H2O, as well as of inorganic salts CuCl2 2H20, CoCl2 6H2O and FeCl3.6H2O of corresponding metal ions. The antiproliferative activity of these compounds was examined in a human melanoma cell line FemX with exposure time of 48 hours by performing two cytotoxicity tests: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and sulforhodamine B (SRB) assay. Among these substances, the ligand H2L.2H2O expressed the greatest antineoplastic activity IC50 = 45.40 microM, while the IC50 of others could not be determined by SRB assay in the examined range of concentrations due to their low activity. FeCl3.6H2O showed stimulatory activity. We have found remarkable discrepancies between the results obtained by MTT assay and SRB assay that influence IC50 value as well as other measures of cytotoxicity, which led to the conlusion of uncertainty of using the MTT assay in evaluation of antineoplastic activity of organometalic complexes and inorganic metal salts.

Trans-platinum complexes as anticancer drugs: recent developments and future prospects.

Cisplatin represents one of the most potent drugs available in the cancer chemotherapy for several solid tumors, such as germ cell tumors, ovarian, lung, head and neck, and bladder cancers. Structure-activity relationship studies showed that leaving groups (generally chlorine) and two amine ligands in platinum complexes must be in the cis orientation and that the corresponding trans compounds are inactive. During the 1990's, several groups have reported trans-platinum compounds with in vitro growth inhibitory and in vivo antitumor properties. Some of these complexes were active against tumor cells resistant to cisplatin. More interestingly, there is a difference in cellular and biochemical pharmacology between trans-platinum complexes and cisplatin. Thus, monofunctional adducts might be related to the cytotoxicity of the trans-platinum-iminoether compounds against cis-DDP sensitive/resistant cell lines; unusual structure of long-range interstrand cross-links might be relevant for great effectivity of bifunctional polinuclear trans-platinum(II) compounds against cis-DDP resistant variants. Trans-platinum compounds, appear to follow different pattern of cell killing in comparison to cisplatin, thus giving a reason for optimism in their development as a new class of platinum-based antitumor drugs.

Antiproliferative activity of some cis-/trans-platinum(II) complexes on HeLa cells.

Purpose of this work was to synthesize several cis-/trans- isomer pairs of the platinum(II) complexes, and study the extent and the mode of their antiproliferative activity on HeLa cells. Six platinum(II) isomer pairs have a general formula cis-/trans-[PtA2X2], where A is ligand: ammonia (NH3), pyridine (Py); and X is ligand: chloride ion (Cl-), bromide ion (Br-), iodide ion (I-), thiocyanato ion (SCN-); four compounds have different structural formulas, and these are cis-/trans-[Pt(NH2OH)2(NH3)2]Cl2, and cis-/trans-Pt(Gly)2, where Gly is bidentate glycinato ligand. Results of the MTT assay, showed that six cis- and one trans-platinum(II) complexes exhibited cytotoxicity (IC50) ranging between 5 and 33 microM. Most of the cis-platinum(II) isomers caused significant alteration of cell cycle phases progression, and induced apoptosis in degree that varied among different compounds, as evaluated using flowcytometry and morphological study. Spectrophotometric analysis (AAS) indicated that there is no correlation between intracellular platinum(II) accumulation and cytotoxicity of tested complexes.