Platinum (IV) derivative with adamantylamine-LA-12-represents a new generation of highly efficient anti-cancer drug derived from cisplatin and is currently in the final stage of phase I clinical trials. Understanding the specific mechanisms of its effects on cell cycle is necessary for defining the mode of action of LA-12. In this study, we characterized the ability of LA-12 to induce cell cycle perturbations in ovarian cancer cell line A2780 as compared to equitoxic cisplatin treatment. LA-12 induced a permanent accumulation of A2780 cells in S phase while cisplatin caused G2/M arrest at 24-h time point, where we also detected an increased expression of Gadd45alpha protein. Although both derivatives induced a rapid increase of p53 expression, this was not associated with a down-regulation of Mdm2 protein. Increased expression of p21(Cip1/WAF1) protein and its association with cyclins A and B1 suggested that this cyclin-dependent kinase inhibitor might contribute significantly to the observed perturbations of cell cycle. The results of this study provide insight into the mechanism of action of platinum-based derivative with adamantylamine on cell cycle in ovarian cancer cells. The differences between effects of LA-12 and cisplatin suggest that more attention should be paid to elucidation of modes of action of novel platinum(IV) complexes at cellular level.
- MeSH
- amantadin aplikace a dávkování farmakologie MeSH
- buněčný cyklus účinky léků MeSH
- cisplatina farmakologie MeSH
- financování organizované MeSH
- karcinom farmakoterapie metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory vaječníků farmakoterapie metabolismus MeSH
- organoplatinové sloučeniny farmakologie MeSH
- proliferace buněk účinky léků MeSH
- protein X asociovaný s bcl-2 metabolismus MeSH
- proteiny buněčného cyklu metabolismus MeSH
- protinádorové látky farmakologie MeSH
- protoonkogenní proteiny c-mdm2 metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
OBJECTIVES: The resistance of tumor cells to cisplatin remains a major cause of treatment failure in cancer patients. In this study, the ability of Pt(IV) complex with adamantylamine-LA-12 and its reduced counterpart with lower oxidation state Pt(II)-LA-9 to overcome intrinsic cisplatin resistance was investigated. METHODS: The ovarian adenocarcinoma SK-OV-3 cells were exposed to cisplatin, LA-9, or LA-12 for 72 h and the effects of drug concentrations that caused 10% or 50% inhibition of cell proliferation were determined. After 24-72 h of sustained exposure viability, apoptosis and inhibition of proliferation were analyzed. DNA synthesis and cell cycle analysis were performed simultaneously in order to determine the modulation of cell cycle after platinum complexes treatment. RESULTS: Lung Resistance-related Protein (LRP/MVP) was detected in SK-OV-3 cells but not in the other two ovarian cancer lines with different sensitivity to cisplatin. LRP/MVP overexpression may be an important factor contributing to intrinsic cisplatin resistance. Interestingly, Pt(IV) complex-LA-12 had approximately 2.7-fold lower IC(50) concentration than LA-9 or cisplatin in SK-OV-3 cells. Moreover, LA-12 caused persistent accumulation of cells in S-phase of the cell cycle while LA-9 and cisplatin treatment-induced S-phase arrest was transient and shifted to G(2)/M-phase at later intervals. Apoptosis seemed to be not the dominant type of cell death caused by such the derivatives, but it was the most intensive after LA-12 treatment. CONCLUSIONS: We found strong differences between effects of Pt(IV) complex-LA-12 and Pt(II) derivatives-LA-9 and cisplatin on cytokinetic parameters. Overall, LA-12 but not its reduced Pt(II) counterpart LA-9 is the compound effective in p53 null human ovarian cancer cells and it is able to overcome intrinsic cisplatin resistance in these cells.
- MeSH
- adenokarcinom farmakoterapie metabolismus patologie MeSH
- amantadin analogy a deriváty aplikace a dávkování MeSH
- buněčný cyklus účinky léků MeSH
- buňky - růstové procesy účinky léků MeSH
- chemorezistence MeSH
- cisplatina aplikace a dávkování MeSH
- DNA nádorová biosyntéza MeSH
- financování organizované MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny biosyntéza MeSH
- nádory vaječníků farmakoterapie metabolismus patologie MeSH
- organoplatinové sloučeniny aplikace a dávkování farmakologie MeSH
- poly(ADP-ribosa)polymerasy metabolismus MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie MeSH
- vault ribonucleoprotein particles antagonisté a inhibitory MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- MeSH
- amantadin analogy a deriváty terapeutické užití MeSH
- chemorezistence imunologie účinky léků MeSH
- cisplatina analogy a deriváty imunologie škodlivé účinky MeSH
- financování organizované MeSH
- hodnocení léčiv metody využití MeSH
- lékařská onkologie metody trendy MeSH
- lidé MeSH
- nádorové buněčné linie imunologie metabolismus účinky léků MeSH
- nádory vaječníků farmakoterapie MeSH
- nežádoucí účinky léčiv MeSH
- organoplatinové sloučeniny škodlivé účinky terapeutické užití MeSH
- protinádorové látky škodlivé účinky terapeutické užití toxicita MeSH
- Check Tag
- lidé MeSH
