BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. METHODS: We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. RESULTS: We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. CONCLUSIONS: Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.

• Klíčová slova
• AHR, Biotransformation, CYP1A2, Hepatocellular carcinoma, microRNA,
• MeSH
• biotransformace MeSH
• cytochrom P-450 CYP1A2 metabolismus   MeSH
• down regulace MeSH
• hepatocelulární karcinom * genetika   metabolismus   MeSH
• hepatocyty metabolismus   MeSH
• lidé MeSH
• mikro RNA metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory jater * genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• xenobiotika metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CYP1A2 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A2 MeSH
• mikro RNA MeSH
• MIRN29C microRNA, human MeSH Prohlížeč
• MIRN653 microRNA, human MeSH Prohlížeč
• xenobiotika MeSH

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