Searching for new strategies for effective elimination of human prostate cancer cells, we investigated the cooperative cytotoxic action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two platinum-based complexes, cisplatin or LA-12, and related molecular mechanisms. We demonstrated a notable ability of cisplatin or LA-12 to enhance the sensitivity of several human prostate cancer cell lines to TRAIL-induced cell death via an engagement of mitochondrial apoptotic pathway. This was accompanied by augmented Bid cleavage, Bak activation, loss of mitochondrial membrane potential, activation of caspase-8, -10, -9, and -3, and XIAP cleavage. RNAi-mediated silencing of Bid or Bak in Bax-deficient DU 145 cells suppressed the drug combination-induced cytotoxicity, further underscoring the involvement of mitochondrial signaling. The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. Importantly, we newly demonstrated LA-12-mediated enhancement of TRAIL-induced cell death in cancer cells derived from human patient prostate tumor specimens. Our results provide convincing evidence that employing TRAIL combined with cisplatin/LA-12 could contribute to more effective killing of prostate cancer cells compared to the individual action of the drugs, and offer new mechanistic insights into their cooperative anticancer action.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• cisplatina farmakologie   MeSH
• kaspasa 10 metabolismus   MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádory prostaty metabolismus   patologie   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• protein Bid metabolismus   MeSH
• protein TRAIL metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amantadin MeSH
• BID protein, human MeSH Prohlížeč
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• kaspasa 10 MeSH
• organoplatinové sloučeniny MeSH
• protein Bid MeSH
• protein TRAIL MeSH

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with β-secretase (BACE1) activity, Aβ peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N-methyl-d-aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively Aβ peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.

• Klíčová slova
• Aggregation, Alzheimer's disease, Amyloid, Aβ peptide, Muscarinic/nicotinic acetylcholine receptor antagonist, N-Methyl-d-aspartate receptor antagonist, β-Secretase inhibitor,
• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• amyloidní beta-protein antagonisté a inhibitory   metabolismus   MeSH
• CHO buňky MeSH
• cholinesterasy metabolismus   MeSH
• cílená molekulární terapie MeSH
• Cricetulus MeSH
• dimerizace MeSH
• HEK293 buňky MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• lidé MeSH
• receptor muskarinový M1 antagonisté a inhibitory   metabolismus   MeSH
• receptory cholinergní metabolismus   MeSH
• receptory N-methyl-D-aspartátu metabolismus   MeSH
• sekretasy antagonisté a inhibitory   metabolismus   MeSH
• takrin analogy a deriváty   chemie   farmakologie   MeSH
• Xenopus MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-methoxytacrine MeSH Prohlížeč
• amantadin MeSH
• amyloidní beta-protein MeSH
• cholinesterasy MeSH
• inhibitory enzymů MeSH
• receptor muskarinový M1 MeSH
• receptory cholinergní MeSH
• receptory N-methyl-D-aspartátu MeSH
• sekretasy MeSH
• takrin MeSH

We demonstrated for the first time an outstanding ability of rosiglitazone to mediate a profound enhancement of LA-12-induced apoptosis associated with activation of mitochondrial pathway in human colon cancer cells. This effect was preferentially observed in the G1 cell cycle phase, independent on p53 and PPARγ proteins, and accompanied with significant changes of selected Bcl-2 family protein levels. Further stimulation of cooperative synergic cytotoxic action of rosiglitazone and LA-12 was demonstrated in the cells deficient for PTEN, where mitochondrial apoptotic pathway was more stimulated and G1-phase-associated dying was reinforced. Our results suggest that combined treatment with rosiglitazone and LA-12 might be promising anticancer strategy in colon-derived tumours regardless of their p53 status, and also favourable in those defective in PTEN function.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• energetický metabolismus účinky léků   MeSH
• fosfohydroláza PTEN genetika   MeSH
• HCT116 buňky MeSH
• kontrolní body fáze G1 buněčného cyklu účinky léků   MeSH
• lidé MeSH
• malá interferující RNA MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondrie metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory tračníku farmakoterapie   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• PPAR gama genetika   MeSH
• proliferace buněk účinky léků   MeSH
• RNA interference MeSH
• rosiglitazon MeSH
• synergismus léků MeSH
• thiazolidindiony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• fosfohydroláza PTEN MeSH
• malá interferující RNA MeSH
• nádorový supresorový protein p53 MeSH
• organoplatinové sloučeniny MeSH
• PPAR gama MeSH
• Pten protein, mouse MeSH Prohlížeč
• rosiglitazon MeSH
• thiazolidindiony MeSH

In search for novel strategies in colon cancer treatment, we investigated the unique ability of platinum(IV) complex LA-12 to efficiently enhance the killing effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), and compared it with the sensitizing action of cisplatin. We provide the first evidence that LA-12 primes human colon cancer cells for TRAIL-induced cytotoxicity by p53-independent activation of the mitochondrial apoptotic pathway. The cooperative action of LA-12 and TRAIL was associated with stimulation of Bax/Bak activation, drop of mitochondrial membrane potential, caspase-9 activation, and a shift of the balance among Bcl-2 family proteins in favor of the pro-apoptotic members. In contrast to cisplatin, LA-12 was a potent inducer of ERK-mediated Noxa and BimL protein upregulation, and more effectively enhanced TRAIL-induced apoptosis in the absence of Bax. The cooperative action of LA-12 and TRAIL was augmented following the siRNA-mediated silencing of Mcl-1 in both Bax proficient/deficient cells. We newly demonstrated that LA-12 induced ERK-mediated c-Myc upregulation, and proved that c-Myc silencing inhibited the mitochondrial activation and apoptosis in colon cancer cells treated with LA-12 and TRAIL. The LA-12-mediated sensitization to TRAIL-induced apoptosis was demonstrated in several colon cancer cell lines, further underscoring the general relevance of our findings. The selective action of LA-12 was documented by preferential priming of cancer but not normal colon cancer cells to TRAIL killing effects. Our work highlights the promising potential of LA-12 over cisplatin to enhance the colon cancer cell sensitivity to TRAIL-induced apoptosis, and provides new mechanistic insights into their cooperative action.

• Klíčová slova
• Apoptosis, Cisplatin, Colon cancer, LA-12, TRAIL,
• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   genetika   MeSH
• cisplatina farmakologie   MeSH
• geny p53 MeSH
• HCT116 buňky účinky léků   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádorové buňky kultivované MeSH
• nádory tračníku farmakoterapie   metabolismus   patologie   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• protein Bak metabolismus   MeSH
• protein TRAIL metabolismus   farmakologie   MeSH
• protein X asociovaný s bcl-2 genetika   metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• protoonkogenní proteiny c-myc genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• BAK1 protein, human MeSH Prohlížeč
• BAX protein, human MeSH Prohlížeč
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• organoplatinové sloučeniny MeSH
• protein Bak MeSH
• protein TRAIL MeSH
• protein X asociovaný s bcl-2 MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• protoonkogenní proteiny c-myc MeSH
• TNFSF10 protein, human MeSH Prohlížeč

OBJECTIVES: Therapeutic potential of conventionally used platinum-based drugs in treatment of colorectal tumours has been limited due to high incidence of tumour resistance to them and to their severe side effects. This evokes a search for more suitable anti-cancer drugs. We have compared ability of oxaliplatin and a novel platinum(IV) complex, LA-12, to modulate the cell cycle and induce apoptosis in human colon adenocarcinoma HCT116 wt and p53/p21 null cells, and have investigated molecular mechanisms involved. MATERIALS AND METHODS: Cell cycle-related changes were analysed by flow cytometry (bromodeoxyuridine/propidium iodide staining, histone H3 phosphorylation). Apoptosis was detected using flow cytometry (assays monitoring caspase activity) and fluorescence microscopy (nuclear morphology). Changes in levels of genes/proteins involved in cell cycle and apoptosis regulation were examined by RT-PCR and western blotting. RESULTS: Our results highlight the outstanding ability of LA-12 to induce effective elimination of colon cancer cells independently of p53/p21, and in significantly lower doses compared to oxaliplatin. While oxaliplatin induced p53- and p21-dependent G2 -phase arrest associated with downregulation of cyclin B1 and Cdk1, LA-12 allowed cells to enter M-phase of the cell cycle regardless of p53/p21 status. CONCLUSIONS: Higher malignant cell toxicity and ability to bypass cell cycle arrest important for the cell damage repair suggest LA-12 to be a more effective candidate for elimination of colon tumours from a variety of genetic backgrounds, compared with oxaliplatin.

• MeSH
• adenokarcinom farmakoterapie   genetika   MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   genetika   MeSH
• buněčné dělení účinky léků   genetika   MeSH
• cyklin B1 genetika   MeSH
• HCT116 buňky MeSH
• inhibitor p21 cyklin-dependentní kinasy genetika   MeSH
• lidé MeSH
• mitóza účinky léků   genetika   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory tračníku farmakoterapie   genetika   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• oxaliplatin MeSH
• proliferace buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• CDKN1A protein, human MeSH Prohlížeč
• cyklin B1 MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• nádorový supresorový protein p53 MeSH
• organoplatinové sloučeniny MeSH
• oxaliplatin MeSH

PURPOSE: This study compared the pharmacokinetics, tissue distribution, and urinary excretion of platinum in rats after single oral doses of LA-12 and satraplatin. METHODS: Both platinum derivatives were administered to male Wistar rats as suspensions in methylcellulose at four equimolar doses within the range of 37.5-300 mg LA-12/kg body weight. Blood sampling was performed until 72 h, and plasma and plasma ultrafiltrate were separated. Moreover, urine was collected until 72 h, and kidney and liver tissue samples were obtained at several times after administration. Platinum was measured by atomic absorption spectrometry. The pharmacokinetics of platinum was analyzed by population modelling and post hoc Bayesian estimation as well as using non-compartmental pharmacokinetic analysis of the mean concentration-time curves. RESULTS: Platinum was detected in all plasma and ultrafiltrate samples 15 min after oral administration of both compounds and peaked between 3-4 h and 1-3 h, respectively. Similar for LA-12 and satraplatin, the C (max) and AUC values of plasma and ultrafiltrate platinum increased less than in proportion to dose. The mean C (max) and AUC values of plasma platinum observed after administration of LA-12 were from 0.84 to 2.5 mg/l and from 20.2 to 75.9 mg h/l. For ultrafiltrate platinum, the corresponding ranges were 0.16-0.78 mg/l and 0.63-1.8 mg h/l, respectively. The AUC of plasma platinum was higher after satraplatin (P < 0.001). However, administration of LA-12 resulted in significantly higher AUC values of ultrafiltrate platinum after the doses of 150 mg and 300 mg/kg (P < 0.01), respectively, and the C (max) values were significantly higher starting from the dose of 75 mg/kg LA-12 and upward (P < 0.01). Cumulative 72-h urinary recovery of platinum dose was below 5% for both compounds, and it decreased with the dose of satraplatin (P < 0.01), while a numerical decrease was observed after administration of LA-12 that did not reach statistical significance (P = 0.41). The renal clearance of free platinum was similar regardless of the dose and compound administered. Platinum concentrations in the liver homogenate exceeded those in the kidney. Distribution of platinum to tissues was higher after LA-12 compared to satraplatin. The difference in kidney platinum increased with dose and was twofold after 350 mg/kg LA-12. Liver platinum was twofold higher after LA-12 across all four doses. CONCLUSIONS: In conclusion, this first comparative pharmacokinetic study with LA-12 and satraplatin shows that characteristics of platinum exposure evaluated in the plasma, plasma ultrafiltrate and kidney and liver tissues increase less than in proportion to dose following a single-dose administration of 37.5-300 mg/kg to Wistar rats. These findings together with the dose-related elevation in the pharmacokinetic characteristics V/F and CL/F of platinum and ultrafiltrate platinum as well as a drop in platinum urinary recovery are consistent with a dose-related decrease in the extent of oral bioavailability most likely due to saturable intestinal absorption.

• MeSH
• amantadin aplikace a dávkování   analogy a deriváty   farmakokinetika   moč   MeSH
• antitumorózní látky aplikace a dávkování   farmakokinetika   moč   MeSH
• aplikace orální MeSH
• Bayesova věta MeSH
• biologické modely MeSH
• krysa rodu Rattus MeSH
• organoplatinové sloučeniny aplikace a dávkování   farmakokinetika   moč   MeSH
• potkani Wistar MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• organoplatinové sloučeniny MeSH
• satraplatin MeSH Prohlížeč

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) can selectively trigger apoptosis in various cancer cell types. However, many cancer cells are resistant to death receptor-mediated apoptosis. Combination therapy with platinum complexes may affect TRAIL-induced signaling via modulation of various steps in apoptotic pathways. Here, we show that cisplatin or a more potent platinum(IV) complex LA-12 used in 20-fold lower concentration enhanced killing effects of TRAIL in human colon and prostate cancer cell lines via stimulation of caspase activity and overall apoptosis. Both platinum complexes increased DR5 surface expression in colon cancer cells. Small interfering RNA-mediated DR5 silencing rescued cells from sensitizing effects of platinum drugs on TRAIL-induced caspase-8 activation and apoptosis, showing the functional importance of DR5 in the effects observed. In addition, both cisplatin and LA-12 triggered the relocalization of DR4 and DR5 receptors to lipid rafts and accelerated internalization of TRAIL, which may also affect TRAIL signaling. Collectively, modulations of the initial steps of the extrinsic apoptotic pathway at the level of DR5 and plasma membrane are important for sensitization of colon and prostate cancer cells to TRAIL-induced apoptosis mediated by LA-12 and cisplatin.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• apoptóza účinky léků   fyziologie   MeSH
• cisplatina farmakologie   MeSH
• fluorescenční protilátková technika MeSH
• konfokální mikroskopie MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• protein TRAIL metabolismus   MeSH
• průtoková cytometrie MeSH
• RNA interference MeSH
• separace buněk MeSH
• signální transdukce účinky léků   fyziologie   MeSH
• TRAIL receptory metabolismus   MeSH
• transport proteinů účinky léků   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• organoplatinové sloučeniny MeSH
• protein TRAIL MeSH
• TRAIL receptory MeSH

In this study, we characterized the effects of LA-12 on tumor cell lines possessing wild type p53 and on p53-deficient/mutant cell lines and the results were compared to those obtained using cisplatin. We have determined changes of p53 levels, of its transcriptional activity, of its posttranscriptional modifications and the effect of the treatment on the cell cycle, on the induction of apoptosis and on gene expression. LA-12 induces weak accumulation of both transcriptionally active p53 tumor suppressor and of p21(WAF1/CIP1) protein. LA-12 and cisplatin also significantly differ in their effects on apoptosis and cell cycle and on gene expression spectra in studied cell lines. LA-12 induces higher apoptosis levels in comparison with those induced by cisplatin, especially in p53-deficient H1299 cells and in MCF-7DD cells with transcriptionally inactive p53. We suggest that LA-12-mediated apoptosis is not fully dependent on p53. This confirms the therapeutic potential of LA-12 as a more potent cytostatic agent for both tumor cells expressing wild type p53 and for p53-deficient or mutant cells.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• cisplatina farmakologie   MeSH
• geny p53 MeSH
• inhibitor p21 cyklin-dependentní kinasy metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• CDKN1A protein, human MeSH Prohlížeč
• cisplatina MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• nádorový supresorový protein p53 MeSH
• organoplatinové sloučeniny MeSH
• proteiny regulující apoptózu MeSH

BACKGROUND: Cisplatin and its derivatives are commonly used anti-cancer drugs. However, cisplatin has clinical limitations including serious side effects and frequent emergence of intrinsic or acquired resistance. Thus, the novel platinum(IV) complex LA-12 represents a promising treatment modality, which shows increased intracellular penetration resulting in improved cytotoxicity in various cancer cell lines, including cisplatin resistant cells. RESULTS: LA-12 disrupts cellular proliferation regardless of the p53 status in the cells, however the potency of the drug is greatly enhanced by the presence of a functional p53, indicating several mechanisms of action. Similarly to cisplatin, an interaction of LA-12 with molecular chaperone Hsp90 was proposed. Binding of LA-12 to Hsp90 was demonstrated by Hsp90 immunoprecipitation followed by platinum measurement using atomic absorption spectrometry (AAS). An inhibitory effect of LA-12 on Hsp90 chaperoning function was shown by decrease of Hsp90-assisted wild-type p53 binding to p21WAF1 promoter sequence in vitro and by accelerated ubiqutination and degradation of primarily unfolded mutant p53 proteins in cells exposed to LA-12. CONCLUSIONS: To generalize our findings, LA-12 induced degradation of other Hsp90 client proteins such as Cyclin D1 and estrogen receptor was shown and proved as more efficient in comparison with cisplatin. This newly characterised molecular mechanism of action opens opportunities to design new cancer treatment strategy profitable from unique LA-12 properties, which combine DNA damaging and Hsp90 inhibitory effects.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• cisplatina farmakologie   MeSH
• imunoprecipitace MeSH
• inhibitor p21 cyklin-dependentní kinasy účinky léků   metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 účinky léků   metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• proteiny tepelného šoku HSP90 účinky léků   metabolismus   MeSH
• spektrofotometrie atomová MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• CDKN1A protein, human MeSH Prohlížeč
• cisplatina MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• nádorový supresorový protein p53 MeSH
• organoplatinové sloučeniny MeSH
• proteiny tepelného šoku HSP90 MeSH

BACKGROUND: LA-12 is a new platinum (IV) drug with promising cytotoxic effects in a wide range of cancer cell lines. Its confluence-dependent effects were compared with cisplatin (CDDP) and oxaliplatin (L-OHP) in HT-29 cells. MATERIALS AND METHODS: Cytotoxicity was determined by MTT test, eosin exclusion assay, and cell number quantification. The cell cycle was analysed using propidium iodide DNA staining (flow cytometry), apoptosis by phosphatidylserine externalisation (annexin-V assay), mitochondrial membrane potential by flow cytometry, nuclear morphology by means of fluorescence microscopy, and PARP cleavage by Western blotting. RESULTS: While L-OHP and CDDP were practically inactive in the subconfluent cell population, LA-12 showed a similar toxicity in both subconfluent and growing populations. All compounds induced apoptosis, although with different potentials. CONCLUSION: LA-12 was able to overcome confluence-dependent resistance of HT-29 cells observed for other platinum compounds, which may have potential therapeutic use in slowly growing tumours.

• MeSH
• adenokarcinom farmakoterapie   MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčná adheze účinky léků   MeSH
• buňky HT-29 MeSH
• chemorezistence MeSH
• cisplatina farmakologie   MeSH
• lidé MeSH
• nádory tračníku farmakoterapie   patologie   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• oxaliplatin MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• organoplatinové sloučeniny MeSH
• oxaliplatin MeSH