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Oncogene ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616059


Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.

Oncotarget ; 7(5): 5507-20, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26701728


Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases.

Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/efeitos dos fármacos , Cloridrato de Bendamustina/farmacologia , Lectinas Tipo C/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Purinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Lectinas Tipo C/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Células Tumorais Cultivadas
Oncotarget ; 6(26): 22734-49, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-26068951


Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machinery. Consistently, sudemycin exhibits considerable antitumor activity in NOD/SCID/IL2Rγ-/- (NSG) mice engrafted with primary cells from CLL patients. The antileukemic effect of sudemycin involves the splicing modulation of several target genes important for tumor survival, both in SF3B1-mutated and -unmutated cases. Thus, the apoptosis induced by this compound is related to the alternative splicing switch of MCL1 toward its proapoptotic isoform. Sudemycin also functionally disturbs NF-κB pathway in parallel with the induction of a spliced RELA variant that loses its DNA binding domain. Importantly, we show an enhanced antitumor effect of sudemycin in combination with ibrutinib that might be related to the modulation of the alternative splicing of the inhibitor of Btk (IBTK). In conclusion, we provide first evidence that the spliceosome is a relevant therapeutic target in CLL, supporting the use of splicing modulators alone or in combination with ibrutinib as a promising approach for the treatment of CLL patients.

Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cicloexilaminas/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/farmacologia , Pirimidinas/farmacologia , Compostos de Espiro/farmacologia , Adulto , Idoso , Animais , Cicloexilaminas/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Pessoa de Meia-Idade , Mutação , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Processamento de RNA , Compostos de Espiro/administração & dosagem , Spliceossomos/efeitos dos fármacos , Spliceossomos/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
Oncotarget ; 6(25): 21159-72, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26110568


Acadesine is a nucleoside analogue with known activity against B-cell malignancies. Herein, we showed that in mantle cell lymphoma (MCL) cells acadesine induced caspase-dependent apoptosis through turning on the mitochondrial apoptotic machinery. At the molecular level, the compound triggered the activation of the AMPK pathway, consequently modulating known downstream targets, such as mTOR and the cell motility-related vasodilator-stimulated phosphoprotein (VASP). VASP phosphorylation by acadesine was concomitant with a blockade of CXCL12-induced migration. The inhibition of the mTOR cascade by acadesine, committed MCL cells to enter in apoptosis by a translational downregulation of the antiapoptotic Mcl-1 protein. In contrast, Bcl-2 protein levels were unaffected by acadesine and MCL samples expressing high levels of Bcl-2 tended to have a reduced response to the drug. Targeting Bcl-2 with the selective BH3-mimetic agent ABT-199 sensitized Bcl-2high MCL cells to acadesine. This effect was validated in vivo, where the combination of both agents displayed a more marked inhibition of tumor outgrowth than each drug alone. These findings support the notions that antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and that the combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients.

Aminoimidazol Carboxamida/análogos & derivados , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Moléculas de Adesão Celular/metabolismo , Linfoma de Célula do Manto/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ribonucleosídeos/administração & dosagem , Sulfonamidas/administração & dosagem , Actinas/química , Aminoimidazol Carboxamida/administração & dosagem , Animais , Apoptose , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular , Quimiocina CXCL12/metabolismo , Quimiotaxia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos SCID , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Transplante de Neoplasias
Oncotarget ; 5(16): 6788-800, 2014 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-25216518


Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL.

Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Aminopiridinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL12/metabolismo , Everolimo , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/farmacologia , Interleucina-4/antagonistas & inibidores , Interleucina-4/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Linfoma de Célula do Manto/metabolismo , Morfolinas/farmacologia , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Transcriptoma , Microambiente Tumoral/efeitos dos fármacos