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1.
Mol Cancer Ther ; 11(8): 1758-69, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22848094

RESUMO

There is a critical need for efficacious therapeutic strategies to improve the outcome of patients afflicted by malignant peripheral nerve sheath tumors (MPNST). Multiple lines of evidence suggest a role for deregulated phosphoinositide 3-kinase (PI3K)/mTOR signaling in MPNST, making this axis an attractive target for therapeutic manipulation. On the basis of previous observations obtained from in vitro experimentation, here we aimed to assess the effects of PI3K/mTOR blockade on MPNST growth in vivo. The anti-MPNST impact of XL765, a dual PI3K/mTOR inhibitor currently being evaluated in human cancer clinical trials, was tested in two human MPNST xenograft models (STS26T and MPNST724) and an experimental model of pulmonary metastasis (STS26T). XL765 abrogated human MPNST local and metastatic growth in severe combined immunodeficient mice. Notably, this therapeutic approach failed to induce apoptosis in MPNST cells but rather resulted in marked productive autophagy. Importantly, genetic and pharmacologic autophagy blockade reversed apoptotic resistance and resulted in significant PI3K/mTOR inhibition-induced MPNST cell death. The addition of the autophagy inhibitor, chloroquine, to the therapeutic regimen of MPNST xenografts after pretreatment with XL765 resulted in superior antitumor effects as compared with either agent alone. Together, preclinical studies described here expand our previous findings and suggest that PI3K/mTOR inhibition alone and (most importantly) in combination with autophagy blockade may comprise a novel and efficacious therapy for patients harboring MPNST.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Neoplasias de Bainha Neural/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Quinoxalinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Humanos , Camundongos , Neoplasias de Bainha Neural/tratamento farmacológico , Neoplasias de Bainha Neural/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Oncol Rep ; 26(3): 687-93, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21617882

RESUMO

Quercetin is the most abundant polyphenolic flavonoid found in plants. Several studies suggest that it has potent anticancer effects. The present study examines the apoptosis-inducing activity and the underlying mechanism of action of quercetin in a methotrexate (MTX)-resistant osteosarcoma model. Our results showed that quercetin inhibited cell viability in a dose-dependent manner and there was no cross-resistance between MTX and quercetin in U2-OS/MTX300 cells. The induction of apoptosis was observed by flow cyto-metry and fluorescence staining experiments. Quercetin-induced apoptosis was accompanied by a significant reduction of mitochondrial membrane potential, release of mitochondrial cytochrome c to the cytosol, activation of caspase-3, down-regulation of Bcl-2, p-Bad and up-regulation of Bax. A remarkable dephospho-rylation of Akt was also detected after quercetin treatment. Furthermore, transduction with constitutively active Akt protected against the quercetin-induced dephosphorylation of Akt and Bad as well as poly(ADP-ribose)polymerase (PARP) degradation, while combined treatment with quercetin and LY294002 enhanced the dephosphorylation of Akt, Bad and PARP cleavage in U2-OS/MTX300 cells. Taken together, our results demonstrate that quercetin-induced apoptosis in the MTX-resistant osteosarcoma cells U2-OS/MTX300 was mediated via mitochondrial dysfunction and dephosphorylation of Akt.


Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Metotrexato/farmacologia , Mitocôndrias/efeitos dos fármacos , Osteossarcoma/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular , Citocromos c/metabolismo , Ativação Enzimática , Humanos , Potencial da Membrana Mitocondrial , Fosforilação , Processamento de Proteína Pós-Traducional
3.
J Biol Chem ; 283(3): 1401-1410, 2008 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-17991744

RESUMO

The small IQ motif proteins PEP-19 (62 amino acids) and RC3 (78 amino acids) greatly accelerate the rates of Ca(2+) binding to sites III and IV in the C-domain of calmodulin (CaM). We show here that PEP-19 decreases the degree of cooperativity of Ca(2+) binding to sites III and IV, and we present a model showing that this could increase Ca(2+) binding rate constants. Comparative sequence analysis showed that residues 28 to 58 from PEP-19 are conserved in other proteins. This region includes the IQ motif (amino acids 39-62), and an adjacent acidic cluster of amino acids (amino acids 28-40). A synthetic peptide spanning residues 28-62 faithfully mimics intact PEP-19 with respect to increasing the rates of Ca(2+) association and dissociation, as well as binding preferentially to the C-domain of CaM. In contrast, a peptide encoding only the core IQ motif does not modulate Ca(2+) binding, and binds to multiple sites on CaM. A peptide that includes only the acidic region does not bind to CaM. These results show that PEP-19 has a novel acidic/IQ CaM regulatory motif in which the IQ sequence provides a targeting function that allows binding of PEP-19 to CaM, whereas the acidic residues modify the nature of this interaction, and are essential for modulating Ca(2+) binding to the C-domain of CaM.


Assuntos
Calmodulina/metabolismo , Peptídeos/metabolismo , Amidas , Motivos de Aminoácidos , Sequência de Aminoácidos , Cálcio/metabolismo , Calmodulina/química , Sequência Consenso , Cinética , Dados de Sequência Molecular , Peptídeos/química , Ligação Proteica , Conformação Proteica , Mapeamento de Interação de Proteínas , Alinhamento de Sequência
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