Nuclear DNA is the target responsible for anticancer activity of platinum anticancer drugs. Their activity is mediated by altered signals related to programmed cell death and the activation of various signaling pathways. An example is activation of nuclear factor kappaB (NF-κB). Binding of NF-κB proteins to their consensus sequences in DNA (κB sites) is the key biochemical activity responsible for the biological functions of NF-κB. Using gel-mobility-shift assays and surface plasmon resonance spectroscopy we examined the interactions of NF-κB proteins with oligodeoxyribonucleotide duplexes containing κB site damaged by DNA adducts of three platinum complexes. These complexes markedly differed in their toxic effects in tumor cells and comprised highly cytotoxic trinuclear platinum(II) complex BBR3464, less cytotoxic conventional cisplatin and ineffective transplatin. The results indicate that structurally different DNA adducts of these platinum complexes exhibit a different efficiency to affect the affinity of the platinated DNA (κB sites) to NF-κB proteins. Our results support the hypothesis that structural perturbations induced in DNA by platinum(II) complexes correlate with their higher efficiency to inhibit binding of NF-κB proteins to their κB sites and cytotoxicity as well. However, the full generalization of this hypothesis will require to evaluate a larger series of platinum(II) complexes.

• MeSH
• adukty DNA chemie   metabolismus   MeSH
• cisplatina chemie   metabolismus   farmakologie   MeSH
• HEK293 buňky MeSH
• kinetika MeSH
• komplexní sloučeniny chemie   metabolismus   farmakologie   MeSH
• konsenzuální sekvence MeSH
• lidé MeSH
• NF-kappa B chemie   genetika   metabolismus   MeSH
• oligodeoxyribonukleotidy chemie   metabolismus   MeSH
• organoplatinové sloučeniny chemie   toxicita   MeSH
• platina chemie   metabolismus   MeSH
• povrchová plasmonová rezonance MeSH
• protinádorové látky chemie   metabolismus   farmakologie   MeSH
• rekombinantní proteiny biosyntéza   chemie   izolace a purifikace   MeSH
• retardační test MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Trans diiodido platinum(II) complexes bearing the same as well as different aliphatic amines (mixed-amines) have interesting biological activity; cytotoxicity and interactions with some important biological models have already been demonstrated. Herein we described the interaction of such compounds with ct-DNA, supercoiled and linearized plasmid DNA and 5-GMP. Interestingly, UV irradiation of these compounds results in an increase in reactivity towards DNA and 5-GMP in such model systems. Additionally, the cytotoxicity of the trans-Pt(II) complexes towards human cancer cells is noticeably increased when treatment is combined for 90min with UVA-irradiation. With this work we provide evidence that trans diiodido compounds can be activated by UV-light over relatively short treatment times.

• MeSH
• DNA chemie   MeSH
• jodidy chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemie   účinky záření   toxicita   MeSH
• protinádorové látky chemie   účinky záření   toxicita   MeSH
• ultrafialové záření * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A one-step synthetic procedure using the reaction of potassium bis(oxalato)platinate(II) with the corresponding N6-benzyladenosine derivative (nL) provided the [Pt(ox)(nL)₂]∙1.5H₂O oxalato (ox) complexes 1-5, involving the nL molecules as monodentate coordinated N-donor ligands. The complexes were thoroughly characterized by elemental analysis, multinuclear (¹H, ¹³C, ¹⁵N, 1¹⁹⁵Pt) and two dimensional NMR, infrared and Raman spectroscopy, and mass spectrometry, proving their composition and purity as well as coordination of nL through the N7 atom of the purine moiety. Geometry of [Pt(ox)(4FL)₂] (5) was optimized at the B3LYP/LANLTZ/6-311G** level of theory. The complexes were screened for their in vitro cytotoxicity against two human cancer cell lines (HOS osteosarcoma and MCF7 breast adenocarcinoma), but they did not show any effect up to the concentration of 50.0 µM (compounds 1, 2) or 20.0 µM (compounds 3-5).

• MeSH
• adenosin chemie   MeSH
• lidé MeSH
• ligandy * MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemická syntéza   chemie   toxicita   MeSH
• oxaláty chemie   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) and cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza are 3-chloro-7-azaindole and 3-iodo-7-azaindole, respectively) are quite toxic to ovarian tumor cells, with moderately better IC50 values than for cisplatin in the cisplatin-sensitive cell line A2780. We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors with those involved in the mechanism underlying the effects of conventional cisplatin. Our data indicate that the higher cytotoxicity of 1 and 2 originates mainly from their efficient cellular accumulation, different effects at the level of cell cycle regulation, and reduced propensity for DNA adduct repair. Studies of their reactivity toward cellular components reveal efficient binding to DNA, which is typically required for an active platinum drug. Further results suggest that 1 and 2 are capable of circumventing resistance to cisplatin induced by alterations in cellular accumulation and DNA repair. Hence, the latter two factors appear to be responsible for differences in the toxicity of 1 or 2, and cisplatin in tumor cells. The results of this work reinforce the idea that direct analogues of conventional cisplatin-containing halogeno-substituted 7-azaindoles offer much promise for the design of novel therapeutic agents.

• MeSH
• apoptóza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• glutathion chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• oprava DNA MeSH
• organoplatinové sloučeniny chemie   toxicita   MeSH
• poškození DNA účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

cis-Amminedichlorido(cyclohexylamine)platinum(II) (JM118) is an antitumor Pt(II) analogue of cisplatin exhibiting considerably higher activity than cisplatin in human tumor cells. JM118 is also the major metabolite of the first orally administered Pt(IV) drug satraplatin. In an effort to design improved platinum antitumor agents, it is important to elucidate the biochemical factors that affect the cytotoxic properties of existing platinum drugs. Since DNA is considered the major pharmacological target of platinum drugs, the objective in the present work was to understand more fully the DNA binding mode of antitumor JM118. We examined the rate of aquation of the first chloride of bifunctional JM118 and found that it was considerably lower than that of cisplatin; consequently, the rate of the reaction of JM118 with DNA was lower compared to cisplatin. The influence of global modification by JM118 and its major site-specific adducts on DNA conformation by biochemical methods was investigated as well. While examination of the global modification revealed in several cases no substantial differences in the lesions induced by JM118 and cisplatin, DNA bending due to the 1,2-GG intrastrand adduct of JM118 was lower than that of cisplatin. The bending angles afforded by the adducts of JM118 were only slightly affected by the orientation of the cyclohexylamine ligand toward the 3' or 5' direction of the duplex. We also used in vitro assays that make it possible to monitor DNA repair synthesis by cell-free extracts and DNA-protein cross-linking to probe properties of DNA adducts of JM118. These results showed a higher DNA-protein cross-linking efficiency of JM118 and a less efficient removal from DNA of the adducts of JM118 in comparison with cisplatin. Thus, the results of the present work provide additional evidence that DNA binding of JM118 is in several aspects different from that of conventional cisplatin.

• MeSH
• adukty DNA chemie   MeSH
• cirkulární dichroismus MeSH
• cisplatina chemie   toxicita   MeSH
• denaturace nukleových kyselin MeSH
• DNA chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• oprava DNA MeSH
• organoplatinové sloučeniny chemie   toxicita   MeSH
• protinádorové látky chemie   toxicita   MeSH
• sekvence nukleotidů MeSH
• tranzitní teplota MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Earlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(2)(cis-1,4-DACH)] (DACH=diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum-DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin) revealing: (i) improved cytotoxicity (3.4-5.4-fold) of [PtCl(2)(cis-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (approximately 1.5-fold) of [PtCl(2)(cis-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(2)(cis-1,4-DACH)] with glutathione (approximately 1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media (approximately 2-fold); (v) similar sequence preference of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand cross-linking efficiency (6%); (vii) similar bending (32 degrees) and enhanced local unwinding (approximately 1.5-fold) induced in DNA by the major 1,2-GG-intrastrand cross-link; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(2)(cis-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(2)(cis-1,4-DACH)] from DNA.

• MeSH
• buněčná membrána metabolismus   účinky léků   MeSH
• cyklohexylaminy farmakologie   chemie   metabolismus   MeSH
• DNA nádorová metabolismus   MeSH
• glutathion metabolismus   MeSH
• HeLa buňky MeSH
• králíci MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nosiče léků chemie   metabolismus   toxicita   MeSH
• oprava DNA fyziologie   účinky léků   MeSH
• organoplatinové sloučeniny metabolismus   toxicita   MeSH
• protinádorové látky farmakologie   chemie   metabolismus   MeSH
• skot MeSH
• sloučeniny platiny chemie   metabolismus   toxicita   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• srovnávací studie MeSH

ATP-binding drug efflux transporters decrease intracellular concentrations of cytotoxic drugs, causing multidrug resistance in cancer. In this study, we examined possible interactions of ABCG2 transporter with platinum cytotoxic drugs. We demonstrate here an interference of platinum drugs with enhanced green fluorescence protein (EGFP) in the cellular models, where EGFP was employed as a reporter gene. Cytotoxicity of cisplatin (CIP), carboplatin (CAP) and oxaliplatin (OXP) was significantly lowered in MDCKII cells transfected with ABCG2 transporter and EGFP reporter. The IC(50) values in MDCKII-ABCG2 were 25.7, 164 and 165 microM for CIP, CAP and OXP, respectively, whereas IC(50) for the same cytostatics in MDCKII cells were as follows: 15.4, 133 and 50.3 microM. Addition of fumitremorgin C (FTC), a potent ABCG2 inhibitor, significantly suppressed the resistance of MDCKII-ABCG2 to OXP, suggesting that OXP interacts with ABCG2. However, FTC did not change the sensitivity of the cells to CIP and CAP. We assume that EGFP rather than ABCG2 causes the diminished toxicity of the platinum cytostatics in the transfected cells. This hypothesis was confirmed in human Hep2 cells expressing EGFP: using MTT test, IC(50) of 30.0, 247 and 27.9 microM were obtained for CIP, CAP and OXP, respectively, while 12.3, 106 and 20.5 microM were observed in the parent Hep2 cells. Employing neutral red cytotoxicity assay, similar data were obtained (IC(50) 7.73, 685 and 112 microM for CIP, CAP, and OXP, respectively, in the Hep2-EGFP cells and 1.65, 79.4 and 24.5 microM in the parent Hep2 cells). Caspase-3/7 assay revealed lower susceptibility of EGFP expressing Hep2 cells to apoptosis induced by CIP when compared to the parent cell line. We therefore conclude that EGFP in transfected cells interferes with cytotoxicity of platinum drugs by hindering the drug induced apoptosis and could cause misinterpretation of results obtained in cytotoxicity studies.

• MeSH
• ABC transportéry metabolismus   MeSH
• apoptóza účinky léků   MeSH
• biologické modely MeSH
• chemorezistence MeSH
• cisplatina aplikace a dávkování   farmakologie   toxicita   MeSH
• inhibiční koncentrace 50 MeSH
• karboplatina aplikace a dávkování   farmakologie   toxicita   MeSH
• kultivované buňky MeSH
• lidé MeSH
• nádorové proteiny metabolismus   MeSH
• organoplatinové sloučeniny aplikace a dávkování   farmakologie   toxicita   MeSH
• protinádorové látky aplikace a dávkování   farmakologie   toxicita   MeSH
• psi MeSH
• screeningové testy protinádorových léčiv metody   MeSH
• transfekce metody   MeSH
• zelené fluorescenční proteiny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

• Klíčová slova
• platinový derivát LA-12,
• MeSH
• buněčné linie MeSH
• buňky HT-29 * cytologie   účinky léků   MeSH
• cisplatina analogy a deriváty   terapeutické užití   toxicita   MeSH
• farmakologické účinky MeSH
• farmakoterapie metody   trendy   využití   MeSH
• kolorektální nádory farmakoterapie   MeSH
• kultivační techniky MeSH
• lékařská onkologie metody   trendy   MeSH
• lidé MeSH
• organoplatinové sloučeniny terapeutické užití   toxicita   MeSH
• protinádorové látky * terapeutické užití   toxicita   MeSH
• techniky in vitro MeSH
• Check Tag
• lidé MeSH

A series of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA) were prepared and characterized, and their cytotoxic properties against ovarian and colon cancer cells were evaluated. The trans-[PtCl2(NH3)(pip-pip)] x HCl was significantly more potent than cisplatin in all the cisplatin-resistant ovarian cancer cell lines and was nearly as cytotoxic as cisplatin against colon cancer cells. In vivo studies in mice showed that the pip-pip complexes are significantly less toxic than cisplatin. Cisplatin was more efficacious than both trans-[PtCl2(NH3)(pip-pip)] x HCl and trans-[PtCl2(NBA)(pip-pip)] x HCl in the A2780 and A2780cisR tumor xenograft models, consistent with its lower IC50 values in A2780 cells but contrary to the higher IC50 values in A2780cisR cells. In the colon cancer cell studies, trans-[PtCl2(NH3)(pip-pip)] x HCl was slightly less potent than cisplatin in the in vitro studies but had efficacy comparable to that of cisplatin in the in vivo xenograft model.

• MeSH
• aminy chemie   MeSH
• buněčné jádro genetika   MeSH
• chlorid sodný farmakologie   MeSH
• DNA metabolismus   MeSH
• glukosa farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku MeSH
• nádory vaječníků MeSH
• organoplatinové sloučeniny * farmakokinetika   farmakologie   chemická syntéza   toxicita   MeSH
• piperidiny * farmakokinetika   farmakologie   chemická syntéza   toxicita   MeSH
• protinádorové látky * farmakokinetika   farmakologie   chemická syntéza   toxicita   MeSH
• rozpouštědla MeSH
• rozpustnost MeSH
• screeningové testy protinádorových léčiv MeSH
• transplantace heterologní MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Replacement of one ammine in clinically ineffective trans-[PtCl2(NH3)2] (transplatin) by a planar N-heterocycle, thiazole, results in significantly enhanced cytotoxicity. Unlike 'classical' cisplatin {cis-[PtCl2(NH3)2]} or transplatin, modification of DNA by this prototypical cytotoxic transplatinum complex trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) leads to monofunctional and bifunctional intra or interstrand adducts in roughly equal proportions. DNA fragments containing site-specific bifunctional DNA adducts of trans-PtTz were prepared. The structural distortions induced in DNA by these adducts and their consequences for high-mobility group protein recognition, DNA polymerization and nucleotide excision repair were assessed in cell-free media by biochemical methods. Whereas monofunctional adducts of trans-PtTz behave similar to the major intrastrand adduct of cisplatin [J. Kasparkova, O. Novakova, N. Farrell and V. Brabec (2003) Biochemistry, 42, 792-800], bifunctional cross-links behave distinctly differently. The results suggest that the multiple DNA lesions available to trans-planaramine complexes may all contribute substantially to their cytotoxicity so that the overall drug cytotoxicity could be the sum of the contributions of each of these adducts. However, acquisition of drug resistance could be a relatively rare event, since it would have to entail resistance to or tolerance of multiple, structurally dissimilar DNA lesions

• MeSH
• adukty DNA chemie   metabolismus   MeSH
• cisplatina chemie   toxicita   MeSH
• DNA biosyntéza   MeSH
• financování vládou MeSH
• konformace nukleové kyseliny MeSH
• oprava DNA MeSH
• organoplatinové sloučeniny chemie   toxicita   MeSH
• proteiny s vysokou pohyblivostí metabolismus   MeSH
• protinádorové látky chemie   toxicita   MeSH
• reagencia zkříženě vázaná chemie   toxicita   MeSH
• thiazoly chemie   toxicita   MeSH