RÉSUMÉ
Dysregulation of microRNAs (miRs) has been linked to several types of cancer. In the present study, we investigated the expression of miR-181a in different leukemia cell lines and healthy hematopoietic cells, as well as its influence on cell proliferation, metabolic activity and potential targets. Expression of miR-181a differed between various leukemia cell lines and mature blood cells. Inhibition of miR 181a expression in T- and B-Acute Lymphoblastic Leukemia (ALL) cells revealed an influence on the potential targets High-Mobility-Group-Protein B1 (HMGB1) and Cluster of Differentiation 4 (CD4). Overexpression of miR-181a in AML cells led to a significant decrease in cell proliferation and metabolic activity. The present data indicate a possible role of this specific miRNA in immunogenicity.
Sujet(s)
Antigènes CD4/biosynthèse , Régulation de l'expression des gènes/génétique , Protéine HMGB1/biosynthèse , Leucémies/génétique , Leucémies/métabolisme , microARN/génétique , Technique de Western , Antigènes CD4/génétique , Lignée cellulaire tumorale , Séparation cellulaire , Électroporation , Cytométrie en flux , Analyse de profil d'expression de gènes , Protéine HMGB1/génétique , Humains , Réaction de polymérisation en chaine en temps réelRÉSUMÉ
Indolylmaleimides display a broad spectrum of biological activity and offer great opportunity to influence several aspects of cell fate, as proliferation and differentiation. In this study we describe the effect of PDA-66, a newly synthesised indolylmaleimide, showing a strong dose dependent anti-proliferative effect on immortalised human progenitor and cancer cells. We demonstrated a highly depolymerizing effect on in vitro tubulin assembly and conclude that PDA-66 acts as microtubule destabilising agent. In addition we found that PDA-66 induces mitotic arrest of cells in the G2/M phase of the cell cycle. Subsequently cells undergo apoptosis, indicating the major mechanism of the anti-proliferative effect. To prove a potential anti-cancer activity of PDA-66 we examined the effect of PDA-66 on human SH-SY5Y neuroblastoma and A-459 lung cancer cells, showing a significant reduction in cancer cell proliferation in a dose dependent manner. Thus PDA-66 is a new anti-mitotic compound with an indole-core with the potential to be used for cancer therapy.
Sujet(s)
Apoptose/effets des médicaments et des substances chimiques , Indoles/pharmacologie , Maléimides/pharmacologie , Microtubules/effets des médicaments et des substances chimiques , Mitose/effets des médicaments et des substances chimiques , Tumeurs/anatomopathologie , Cellules souches/effets des médicaments et des substances chimiques , Humains , Immunohistochimie , Microtubules/métabolisme , Tumeurs/métabolisme , Cellules souches/cytologie , Tubuline/métabolismeRÉSUMÉ
BACKGROUND: Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches. MATERIALS AND METHODS: ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa). RESULTS: NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G(0)/G(1) arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells. CONCLUSION: NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Imidazoles/pharmacologie , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Quinoléines/pharmacologie , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Processus de croissance cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Cytarabine/administration et posologie , Dexaméthasone/administration et posologie , Doxorubicine/administration et posologie , Résistance aux médicaments antinéoplasiques , Synergie des médicaments , Humains , Imidazoles/administration et posologie , Cellules Jurkat , Leucémie B/traitement médicamenteux , Leucémie B/enzymologie , Leucémie B/métabolisme , Leucémie B/anatomopathologie , Protéine oncogène v-akt/antagonistes et inhibiteurs , Protéine oncogène v-akt/métabolisme , Phosphatidylinositol 3-kinase/métabolisme , Inhibiteurs des phosphoinositide-3 kinases , Leucémie-lymphome lymphoblastique à précurseurs B et T/enzymologie , Leucémie-lymphome lymphoblastique à précurseurs B et T/métabolisme , Leucémie-lymphome lymphoblastique à précurseurs T/traitement médicamenteux , Leucémie-lymphome lymphoblastique à précurseurs T/enzymologie , Leucémie-lymphome lymphoblastique à précurseurs T/métabolisme , Leucémie-lymphome lymphoblastique à précurseurs T/anatomopathologie , Quinoléines/administration et posologie , Transduction du signal , Sérine-thréonine kinases TOR/antagonistes et inhibiteurs , Sérine-thréonine kinases TOR/métabolismeRÉSUMÉ
BACKGROUND: Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. METHODS: ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. RESULTS: Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. CONCLUSION: Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells.