Structural properties of plasmid DNA and model lipid membrane treated with newly synthesized platinum(II) complex cis-[PtCl2{P(CH2CH2COOH)3}2] (cis-DTCEP for short) were studied and compared with effects of anticancer drug cisplatin, cis-[Pt(NH3)2Cl2] (cis-DDP for short). Time Correlated Single Photon Counting Fluorescence Correlation Spectroscopy (TCSPC-FCS) was employed to study interactions between those platinum complexes and DNA. The TCSPC-FCS results suggest that bonding of cis-DTCEP derivative to DNA leads to plasmid strain realignment towards much more compact structure than in the case of cis-DDP. Application of both differential scanning calorimetry and infrared spectroscopy to platinum complexes/DPPC showed that cis-DTCEP slightly increases the phospholipid's main phase transition temperature resulting in decreased fluidity of the model membrane. The newly investigated compound-similarly to cis-DDP-interacts mainly with the DPPC head group however not only by the means of electrostatic forces: this compound probably enters into hydrophilic region of the lipid bilayer and forms hydrogen bonds with COO groups of glycerol and PO2- group of DPPC.
Terapia zhubných nádorových ochorení patrí medzi najstaršie a zároveň najperspektívnejšie oblasti aplikácie zlúčenín kovov v terapii. Druhá časť prehľadu o metalofarmakách sa zameriava na dejinný vývoj a súčasné využitie komplexných zlúčenín v terapii rakoviny. Najprv sa venuje najznámejšiemu a najúspešnejšiemu liečivu spomedzi metalofarmák – cisplatine. Po stručnom náčrte objavu antineoplastických vlastností tejto zlúčeniny sa zaoberá jej chemickými vlastnosťami, toxicitou, klinickými aplikáciami, mechanizmom účinku a vývojom rezistencie. V ďalšom sú diskutované tiež komplexy iných kovov ako potenciálne chemoterapeutiká, ako aj perspektívne smery výskumu v tejto oblasti. Tento stručný prehľad má za cieľ poskytnúť základnú orientáciu v tejto problematike pre farmaceutov i chemikov, ako aj ostatných záujemcov o danú oblasť z radov odbornej verejnosti.
Therapy of malignant tumors is among the oldest and at the same time the most promising application areas of therapeutic metal complexes. The second part of our survey on metallopharmaceuticals deals with historical development and current state of coordination compounds in cancer therapy. It starts with the most famous and most successful metallodrug – cisplatin. After a brief account of the discovery of the anticancer properties of this substance follows the discussion of its chemical properties, toxicity, clinical application and resistance. Hereafter, complexes of other metals along with innovative research directions are addressed. The aim of this brief survey is to provide basic overview of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public.
- MeSH
- Chemistry, Bioinorganic MeSH
- Cisplatin therapeutic use MeSH
- Drug Therapy methods MeSH
- Coordination Complexes therapeutic use MeSH
- Metals * therapeutic use MeSH
- Humans MeSH
- Neoplasms * drug therapy MeSH
- Platinum therapeutic use MeSH
- Ruthenium therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
[Pt(L)(2)(ox)] (1), [Pt(2-OMeL)(2)(ox)] (2), [Pt(3-OMeL)(2)(ox)] (3), [Pt(2,3-diOMeL)(2)(ox)] (4), [Pt(2,4-diOMeL)(2)(ox)] (5), [Pt(3,4-diOMeL)(2)(ox)] (6) and [Pt(3,5-diOMeL)(2)(ox)].4H(2)O (7) platinum(II) oxalato (ox) complexes were synthesized using the reaction of potassium bis(oxalato)platinate(II) dihydrate with 2-chloro-N6-(benzyl)-9-isopropyladenine or its benzyl-substituted analogues (nL). The complexes 1-7, which represent the first platinum(II) oxalato complexes involving adenine-based ligands, were fully characterized by various physical methods including multinuclear and two dimensional NMR spectroscopy. A single-crystal X-ray analysis of [Pt(2,4-diOMeL)(2)(ox)].2DMF (5.2DMF; DMF=N,N'-dimethylformamide), proved the slightly distorted square-planar geometry in the vicinity of the Pt(II) ion with one bidentate-coordinated oxalate dianion and two adenine derivatives (nL) coordinated to the Pt(II) centre through the N7 atom of an adenine moiety, thereby giving a PtN(2)O(2) donor set. In vitro cytotoxicity of the prepared complexes was tested by an MTT assay against osteosarcoma (HOS) and breast adenocarcinoma (MCF7) human cancer cell lines. The best results were achieved for the complexes 2 and 5 in the case of both cell lines, whose IC(50) values equalled 3.6+/-1.0, and 4.3+/-2.1microM (for 2), and 5.4+/-3.8, and 3.6+/-2.1microM (for 5), respectively. The IC(50) equals 9.2+/-1.5microM against MCF7 cells in the case of 1. The in vitro cytotoxicity of the mentioned complexes significantly exceeded commercially used platinum-based anticancer drugs cisplatin (34.2+/-6.4microM and 19.6+/-4.3microM) and oxaliplatin (>50.0microM for both cancer cell lines).
- MeSH
- Adenine chemistry MeSH
- Cisplatin pharmacology MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds chemical synthesis chemistry pharmacology MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Twelve steroidal platinum(II) complexes were synthesized by reaction of potassium tetrachloroplatinate with steroidal esters of L-methionine and L-histidine. The steroidal esters coordinated as bidentate ligands via S and N donor atoms of L-methionine and via two N donor atoms of L-histidine. Cholesterol, cholestanol, diosgenine, pregnenolone, dehydroepiandrosterone, testosterone, estrone, and estradiol were used as the steroidal compounds. The esters and complexes prepared were characterized by infrared, mass, and (1)H NMR spectroscopy and elemental analysis. Platinum complexes were tested for in vitro cytotoxicity against several cancer cell lines: T-lymphoblastic leukemia CEM, breast carcinoma MCF-7, lung carcinoma A-549, multiple myeloma RPMI 8226, and one normal cell line human fibroblast BJ.
- MeSH
- Esters chemical synthesis chemistry toxicity MeSH
- Financing, Organized MeSH
- Histidine chemistry MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Methionine chemistry MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Platinum chemistry MeSH
- Steroids chemistry MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
In vitro antitumour activity of the [Pt(ox)(L(n))(2)] (1-7) and [Pd(ox)(L(n))(2)] (8-14) oxalato (ox) complexes involving N6-benzyl-9-isopropyladenine-based N-donor carrier ligands (L(n)) against ovarian carcinoma (A2780), cisplatin resistant ovarian carcinoma (A2780cis), malignant melanoma (G-361), lung carcinoma (A549), cervix epitheloid carcinoma (HeLa), breast adenocarcinoma (MCF7) and osteosarcoma (HOS) human cancer cell lines was studied. Some of the tested complexes were even several times more cytotoxic as compared with cisplatin employed as a positive control. The improved cytotoxic effect was demonstrated for the platinum(II) complexes 3 (IC(50)=3.2+/-1.0 microM and 3.2+/-0.6 microM) and 5 (IC(50)=4.0+/-1.0 microM and 4.1+/-1.4 microM) against A2780 and A2780cis, as compared with 11.5+/-1.6 microM, and 30.3+/-6.1 microM determined for cisplatin, respectively. The significant in vitro cytotoxicity against MCF7 (IC(50)=8.2+/-3.8 microM for 12) and A2780 (IC(50)=5.4+/-1.2 microM for 14) was evaluated for the palladium(II) oxalato complexes, which again exceeded cisplatin, whose IC(50) equalled 19.6+/-4.3 microM against the MCF7 cells. Selected complexes were also screened for their in vitro cytotoxic effect in primary cultures of human hepatocytes and they were found to be non-hepatotoxic.
- MeSH
- Adenine analogs & derivatives chemistry MeSH
- Cisplatin pharmacology MeSH
- HeLa Cells MeSH
- Hepatocytes cytology drug effects MeSH
- Inhibitory Concentration 50 MeSH
- Carboplatin pharmacology MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Organometallic Compounds chemical synthesis chemistry pharmacology MeSH
- Organoplatinum Compounds pharmacology MeSH
- Palladium chemistry MeSH
- Platinum chemistry MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
OBJECTIVES: The resistance of tumor cells to cisplatin remains a major cause of treatment failure in cancer patients. In this study, the ability of Pt(IV) complex with adamantylamine-LA-12 and its reduced counterpart with lower oxidation state Pt(II)-LA-9 to overcome intrinsic cisplatin resistance was investigated. METHODS: The ovarian adenocarcinoma SK-OV-3 cells were exposed to cisplatin, LA-9, or LA-12 for 72 h and the effects of drug concentrations that caused 10% or 50% inhibition of cell proliferation were determined. After 24-72 h of sustained exposure viability, apoptosis and inhibition of proliferation were analyzed. DNA synthesis and cell cycle analysis were performed simultaneously in order to determine the modulation of cell cycle after platinum complexes treatment. RESULTS: Lung Resistance-related Protein (LRP/MVP) was detected in SK-OV-3 cells but not in the other two ovarian cancer lines with different sensitivity to cisplatin. LRP/MVP overexpression may be an important factor contributing to intrinsic cisplatin resistance. Interestingly, Pt(IV) complex-LA-12 had approximately 2.7-fold lower IC(50) concentration than LA-9 or cisplatin in SK-OV-3 cells. Moreover, LA-12 caused persistent accumulation of cells in S-phase of the cell cycle while LA-9 and cisplatin treatment-induced S-phase arrest was transient and shifted to G(2)/M-phase at later intervals. Apoptosis seemed to be not the dominant type of cell death caused by such the derivatives, but it was the most intensive after LA-12 treatment. CONCLUSIONS: We found strong differences between effects of Pt(IV) complex-LA-12 and Pt(II) derivatives-LA-9 and cisplatin on cytokinetic parameters. Overall, LA-12 but not its reduced Pt(II) counterpart LA-9 is the compound effective in p53 null human ovarian cancer cells and it is able to overcome intrinsic cisplatin resistance in these cells.
- MeSH
- Adenocarcinoma drug therapy metabolism pathology MeSH
- Amantadine analogs & derivatives administration & dosage MeSH
- Cell Cycle drug effects MeSH
- Cell Growth Processes drug effects MeSH
- Drug Resistance, Neoplasm MeSH
- Cisplatin administration & dosage MeSH
- DNA, Neoplasm biosynthesis MeSH
- Financing, Organized MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Neoplasm Proteins biosynthesis MeSH
- Ovarian Neoplasms drug therapy metabolism pathology MeSH
- Organoplatinum Compounds administration & dosage pharmacology MeSH
- Poly(ADP-ribose) Polymerases metabolism MeSH
- Antineoplastic Combined Chemotherapy Protocols pharmacology MeSH
- Vault Ribonucleoprotein Particles antagonists & inhibitors MeSH
- Blotting, Western MeSH
- Check Tag
- Humans MeSH
- Female MeSH
The platinum(II) malonato (Mal) and decanoato (Dec) complexes of the general formulas [Pt(Mal)(naza)2] (1-3) and cis-[Pt(Dec)2(naza)2] (4-7) were prepared, characterized and tested for their in vitro cytotoxicity against cisplatin-sensitive (A2780) and cisplatin-resistant (A2780R) human ovarian carcinoma cell lines and non-cancerous human lung fibroblasts (MRC-5); naza=halogeno-derivatives of 7-azaindole. Complexes 1-7 effectively overcome the acquired resistance of ovarian carcinoma cells to cisplatin. Complexes 2 (IC50=26.6±8.9μM against A2780 and 28.9±6.7μM against A2780R), 4 (IC50=14.5±0.6μM against A2780 and 14.5±3.8μM against A2780R) and 5 (IC50=13.0±1.1μM against A2780 and 13.6±4.9μM against A2780R) indicated decreased toxicity against healthy MRC-5 cells (IC50>50.0μM for 2 and >25.0μM for 4 and 5). The representative complexes 2 and 4 showed mutually different effect on the A2780 cell cycle at IC50 concentrations after 24h exposure. Concretely, the complex 2 caused cell cycle arrest at G0/G1 phase, while 4 induced cell death by apoptosis with high population of cells in sub-G1 cell cycle phase. The hydrolysis and interactions of the selected complexes with biomolecules (glutathione (GSH) and guanosine monophosphate (GMP)) were also studied by means of (1)H NMR and ESI+ mass spectra.
- MeSH
- Cell Line MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Cisplatin chemistry MeSH
- Epithelial Cells drug effects pathology MeSH
- Fibroblasts cytology drug effects MeSH
- Glutathione chemistry MeSH
- Indoles chemistry MeSH
- Inhibitory Concentration 50 MeSH
- Coordination Complexes chemical synthesis pharmacology MeSH
- G1 Phase Cell Cycle Checkpoints drug effects MeSH
- Guanosine Monophosphate chemistry MeSH
- Carboxylic Acids chemistry MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds chemical synthesis pharmacology MeSH
- Antineoplastic Agents chemical synthesis pharmacology MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
A substitution of the ammine ligands of cisplatin, cis-[Pt(NH3)2Cl2], for cyclin dependent kinase (CDK) inhibitor bohemine (boh), [2-(3-hydroxypropylamino)-6-benzylamino-9-isopropylpurine], results in a compound, cis-[Pt(boh)2Cl2] (C1), with the unique anticancer profile which may be associated with some features of the damaged DNA and/or its cellular processing (Travnicek Z et al. (2003) J Inorg Biochem94, 307-316; Liskova B (2012) Chem Res Toxicol25, 500-509). A combination of biochemical and molecular biology techniques was used to establish mechanistic differences between cisplatin and C1 with respect to the DNA damage they produce and their interactions with critical DNA-binding proteins, DNA-processing enzymes and glutathione. The results show that replacement of the NH3 groups in cisplatin by bohemine modulates some aspects of the mechanism of action of C1. More specifically, the results of the present work are consistent with the thesis that, in comparison with cisplatin, effects of other factors, such as: (i) slower rate of initial binding of C1 to DNA; (ii) the lower efficiency of C1 to form bifunctional adducts; (iii) the reduced bend of longitudinal DNA axis induced by the major 1,2-GG intrastrand cross-link of C1; (iv) the reduced affinity of HMG domain proteins to the major adduct of C1; (v) the enhanced efficiency of the DNA adducts of C1 to block DNA polymerization and to inhibit transcription activity of human RNA pol II and RNA transcription; (vi) slower rate of the reaction of C1 with glutathione, may partially contribute to the unique activity of C1.
- MeSH
- DNA drug effects metabolism MeSH
- Transcription, Genetic drug effects MeSH
- HeLa Cells MeSH
- Humans MeSH
- Molecular Conformation MeSH
- Molecular Structure MeSH
- Organoplatinum Compounds chemical synthesis chemistry pharmacology MeSH
- Polymerization drug effects MeSH
- DNA Damage MeSH
- CDC2 Protein Kinase antagonists & inhibitors MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Purines chemistry pharmacology MeSH
- RNA Polymerase II antagonists & inhibitors genetics MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
A series of platinum(II) diiodido complexes containing 7-azaindole derivatives, having the general formula cis-[PtI2(naza)2] (1-8), has been prepared and thoroughly characterized, including X-ray structure analysis of cis-[PtI2(2Me4Claza)2]∙DMF (8∙DMF; 2Me4Claza = 2-methyl-4-chloro-7-azaindole). Complexes showed high in vitro cytotoxicity against nine human cancer cell lines (IC50 ranging from 0.4 to 12.8 μM), including the cisplatin-resistant ovarian cancer cell line (A2780R; IC50 = 1.0-3.5 μM). The results of in vivo testing, using the L1210 lymphocytic leukaemia model, at the equimolar doses of Pt with cisplatin (2 mg/kg) confirmed the activity of complex 8 comparable to cisplatin. From the mechanistic point of view, evaluated ex vivo by Western blot analyses on the samples of isolated tumour tissues, the treatment of the animals with complex 8, contrary to cisplatin, decreased the levels of tumour suppressor p53 and increased significantly the amount of intracellular anti-apoptotic protein MCL-1L (37 kDa). Additionally, the active form of caspase 3 was significantly elevated in the sample of tumour tissues treated with complex 8, indicating that the activation of p53-independent cell-death pathway was initiated. The light and electron microscopy observations of the cancerous tissues revealed necrosis as a dominant mechanism of cell death, followed by scarce signs of apoptosis. The additional results (e.g. in vitro interaction experiments with selected biomolecules, cell cycle perturbations, gel electrophoretic studies on pUC19 plasmid DNA) supported the hypothesis that the complexes might be involved in the mechanism of action quite different from cisplatin.
- MeSH
- Apoptosis drug effects MeSH
- Cell Cycle drug effects MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Cisplatin administration & dosage MeSH
- Indoles administration & dosage chemistry MeSH
- Caspase 3 genetics MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Protein p53 genetics MeSH
- Ovarian Neoplasms drug therapy genetics pathology MeSH
- Organoplatinum Compounds administration & dosage chemistry MeSH
- Plasmids drug effects MeSH
- Cell Proliferation drug effects MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
