Cisplatin and doxorubicin are widely used anticancer drugs that cause DNA damage, which activates the ATM-Chk2-p53 pathway in cancer cells. This activation leads to cell cycle block or apoptosis, depending on the nature of the DNA damage. In an attempt to enhance the effects of these agents, we inhibited ATM/ATR and Chk2, which are known upstream regulators of p53. The cancer cell lines A2780 and ARN8, bearing the wild-type p53 protein, were used to study changes in p53 activation and trans-activation. Our results suggest that the G(1)-checkpoint, normally activated by DNA damage, is functionally overcome by the action of kinase inhibitors that sensitize cells to apoptosis. Both inhibitors show these effects, albeit with variable intensity in different cell lines, which is promising for other studies and theoretically for use in clinical practice.

• MeSH
• apoptóza * MeSH
• ATM protein MeSH
• checkpoint kinasa 2 MeSH
• cisplatina farmakologie   MeSH
• DNA vazebné proteiny antagonisté a inhibitory   metabolismus   MeSH
• down regulace MeSH
• doxorubicin farmakologie   MeSH
• G0 fáze MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové supresorové proteiny antagonisté a inhibitory   metabolismus   MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• poškození DNA * MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• proteiny buněčného cyklu antagonisté a inhibitory   metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• průtoková cytometrie MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• ATR protein, human MeSH Prohlížeč
• checkpoint kinasa 2 MeSH
• CHEK2 protein, human MeSH Prohlížeč
• cisplatina MeSH
• DNA vazebné proteiny MeSH
• doxorubicin MeSH
• inhibitory proteinkinas MeSH
• nádorové supresorové proteiny MeSH
• nádorový supresorový protein p53 MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH
• protinádorové látky 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
• 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
• protinádorové látky farmakologie   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
• 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
• protinádorové látky MeSH

Signals through the CD95 surface receptor can specifically induce apoptosis. Some tumour cell lines are sensitive to CD95 signals, and insensitive cells can be converted to a sensitive phenotype if given appropriate treatment. To determine whether the apoptotic response of tumour cells to signalling through CD95 might be enhanced by ionizing irradiation, carcinoma cells were treated with either single-dose or fractionated gamma-irradiation. The response to treatment with an agonist anti-CD95 antibody was enhanced by pretreatment with either a single large dose or daily fractionated radiation. Fractionated irradiation induced cumulative and prolonged up-regulation of CD95 expression in cell lines bearing functional p53. Since two of four cell lines exhibiting heightened responsiveness to CD95-mediated signals following fractionated irradiation express mutant p53 and displayed little or no up-regulation of CD95, enhanced responsiveness did not correlate with p53 status and CD95 up-regulation. Continuous inhibition of CD95/CD95-ligand interactions during fractionated irradiation provided no protective effect to cells, arguing that autologous CD95/CD95-ligand interactions did not contribute to the direct lethal effect of irradiation. We conclude that fractionated gamma-irradiation provides an extended period of time when carcinoma cells are more responsive to CD95-mediated signals in vitro.

• MeSH
• antigeny CD95 genetika   fyziologie   účinky záření   MeSH
• apoptóza účinky záření   MeSH
• DNA nádorová metabolismus   účinky záření   MeSH
• frakcionace dávky záření * MeSH
• HeLa buňky MeSH
• kolorektální nádory MeSH
• koncové značení zlomů DNA in situ MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• nádory prsu MeSH
• osteosarkom MeSH
• regulace genové exprese u nádorů účinky záření   MeSH
• signální transdukce účinky záření   MeSH
• záření gama MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD95 MeSH
• DNA nádorová MeSH