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1.
Molecules ; 20(9): 15893-909, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26340616

ABSTRACT

Despite palliative treatments, glioblastoma (GBM) remains a devastating malignancy with a mean survival of about 15 months after diagnosis. Programmed cell-death is de-regulated in almost all GBM and the re-activation of the mitochondrial apoptotic pathway through exogenous bioactive proteins may represent a powerful therapeutic tool to treat multidrug resistant GBM. We have reported that human Bak protein integrated in Liposomes (LB) was able, in vitro, to activate the mitochondrial apoptotic pathway in colon cancer cells. To evaluate the anti-tumor effects of LB on GBM, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and Western blot analysis were performed on GL26 murine cell line. LB treatment shows a dose-dependent inhibition of cell viability, followed by an up-regulation of Bax and a down-modulation of JNK1 proteins. In GL26-bearing mice, two different routes of administration were tested: intra-tumor and intravenous. Biodistribution, tumor growth and animal survival rates were followed. LB show long-lasting tumor accumulation. Moreover, the intra-tumor administration of LB induces tumor growth delay and total tumor regression in about 40% of treated mice, while the intravenous injection leads to a significant increased life span of mice paralleled by an increased tumor cells apoptosis. Our findings are functional to the design of LB with potentiated therapeutic efficacy for GBM.


Subject(s)
Glioblastoma/drug therapy , Proteolipids/chemistry , bcl-2 Homologous Antagonist-Killer Protein/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Humans , Liposomes , Mice
2.
Int J Cancer ; 124(11): 2728-36, 2009 Jun 01.
Article in English | MEDLINE | ID: mdl-19230027

ABSTRACT

Among thyroid carcinomas, highly aggressive undifferentiated or anaplastic carcinomas still await effective therapeutic strategies. R-roscovitine is a novel cyclin-dependent kinase inhibitor in clinical trials as anti-cancer agent. We have investigated the effects of R-roscovitine on proliferation and apoptosis of 4 thyroid cancer cell lines with different degrees of malignancy. R-roscovitine induced cell cycle arrest in G2/M phase in all cells analyzed possibly by inhibiting the CDK1-cyclin B1 complex. However, the compound was unable to induce a significant cell apoptosis. R-roscovitine has been shown to sensitize cancer cells to TRAIL-induced apoptosis. We report that R-roscovitine sensitized thyroid cell lines to TRAIL-induced apoptosis with the highest degree of synergism observed in the most undifferentiated cancer cells. Apoptosis was associated with the activation of caspases. In thyroid cancers, NF-kappaB is constitutively activated contributing to the proliferation of malignant cells. Accordingly, we observed that R-roscovitine inhibited p65 expression and nuclear translocation. Moreover, IKKbeta over-expression inhibited R-roscovitine- and TRAIL-induced apoptosis. The combined treatment also caused down-regulation of anti-apoptotic proteins transcriptionally regulated by NF-kappaB. Finally, R-roscovitine up-regulated expression of DR5 TRAIL receptors. These results demonstrate that undifferentiated thyroid carcinoma cells can be effectively killed by a combination treatment of subtoxic doses of R-roscovitine and TRAIL. R-roscovitine sensitization of TRAIL-induced apoptosis appears to be mediated by the inhibition of the IKK/NF-KB pathway leading to down-regulation of anti-apoptotic genes and up-regulation of TRAIL death receptors. The combination of R-roscovitine and TRAIL may represent a novel approach to the treatment of anaplastic thyroid carcinomas resistant to conventional chemotherapy.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , I-kappa B Kinase/physiology , NF-kappa B/physiology , Purines/pharmacology , Signal Transduction/drug effects , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Thyroid Neoplasms/drug therapy , Active Transport, Cell Nucleus/drug effects , Carcinoma , Caspase 3/metabolism , Cell Division/drug effects , Cell Line, Tumor , G2 Phase/drug effects , Humans , Receptors, TNF-Related Apoptosis-Inducing Ligand/analysis , Roscovitine , Thyroid Neoplasms/pathology , bcl-X Protein/analysis
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