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

Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes. The combined treatment with SCH900776 and cisplatin or LA-12 results in apparent increase in G1/S phase-related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells. We further show that the cancer cell response to the drug combinations is significantly affected by the p21, p53, and PTEN status. In contrast to their wt counterparts, the p53- or p21-deficient cells treated with SCH900776 and cisplatin or LA-12 enter mitosis and become polyploid, and the senescence phenotype is strongly suppressed. While the cell death induced by SCH900776 and cisplatin or LA-12 is significantly delayed in the absence of p53, the anticancer action of the drug combinations is significantly accelerated in p21-deficient cells, which is associated with stimulation of apoptosis beyond G2/M cell cycle phase. We also show that cooperative killing action of the drug combinations in HCT116 cells is facilitated in the absence of PTEN. Our results indicate that SCH900776 may act as an important modulator of cytotoxic response triggered by platinum-based drugs in colon cancer cells.

• MeSH
• apoptóza účinky léků   MeSH
• buněčný cyklus účinky léků   genetika   MeSH
• checkpoint kinasa 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• cisplatina farmakologie   MeSH
• genový knockout MeSH
• inhibitor p21 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• nádory tračníku farmakoterapie   genetika   metabolismus   patologie   MeSH
• poškození DNA účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• pyrazoly farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• sloučeniny platiny farmakologie   MeSH
• stárnutí buněk účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• checkpoint kinasa 1 MeSH
• CHEK1 protein, human MeSH Prohlížeč
• cisplatina MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• MK-8776 MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• protinádorové látky MeSH
• pyrazoly MeSH
• pyrimidiny MeSH
• sloučeniny platiny MeSH

We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs.

• MeSH
• cisplatina * analogy a deriváty   farmakokinetika   farmakologie   MeSH
• DNA nádorová metabolismus   MeSH
• epigeneze genetická účinky léků   MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků * farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky * farmakokinetika   farmakologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina * MeSH
• DNA nádorová MeSH
• protinádorové látky * 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
• 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
• protinádorové látky farmakologie   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
• 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
• protinádorové látky MeSH
• Pten protein, mouse MeSH Prohlížeč
• rosiglitazon MeSH
• thiazolidindiony MeSH