RESUMO
ABSTRACT: Because multiple myeloma (MM) poses a formidable therapeutic challenge despite recent progress, exploring novel targets is crucial. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) emerges as a promising paracaspase with druggable potential, especially unexplored in MM. Our study provided compelling evidence demonstrating a statistically significant elevation of MALT1 expression in human primary MM cells. Moreover, elevated MALT1 expression was associated with a poorer prognosis in MM. Genetic deletion of MALT1 reduced cell growth, colony formation, and tumor growth in vivo. Pharmacological inhibition with 1 µM of a small-molecular MALT1 inhibitor, Mi-2, effectively inhibited cell growth, inducing mitochondria-dependent apoptotic cell death. Mechanistically, MALT1 inhibition disrupted diverse signal transduction pathways, notably impeding nuclear factor κB (NF-κB). Significantly, the inhibition of MALT1 demonstrated a substantial suppression of NF-κB activation by elevating inhibitor of NF-κB, disrupting the nuclear localization of p65 and c-REL. This effect was observed in both the basal state and when stimulated by B-cell maturation antigen, highlighting the pivotal role of MALT1 inhibition in influencing MM cell survival. It was noteworthy that Mi-2 induces properties associated with immunogenic cell death (ICD), as evidenced by increased calreticulin, adenosine triphosphate release, and high-mobility group protein B1 upregulation, consequently triggering ICD-associated immune activation and enhancing CD8+ T-cell cytotoxicity in vitro. In conclusion, our research highlights MALT1 as a promising druggable target for therapeutic interventions in MM, providing insights into its molecular mechanisms in MM progression.
Assuntos
Antígeno de Maturação de Linfócitos B , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Mieloma Múltiplo , NF-kappa B , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/metabolismo , Animais , Camundongos , Antígeno de Maturação de Linfócitos B/metabolismo , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3-4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy.
Assuntos
Síndromes Neurotóxicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Humanos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Estudos Retrospectivos , Síndrome da Liberação de Citocina , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia Baseada em Transplante de Células e TecidosRESUMO
FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked ß-N-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr432, Ser441, and Ser443 regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer.
Assuntos
Neoplasias da Mama , Cromatina , Humanos , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Epigenômica , Proteínas dos MicrofilamentosRESUMO
BACKGROUND: Glioblastoma (GBM) is a brain tumor with the highest level of malignancy and the worst prognosis in the central nervous system. Mitochondrial metabolism plays a vital role in the occurrence and development of cancer, which provides critical substances to support tumor anabolism. Mito-LND is a novel small-molecule inhibitor that can selectively inhibit the energy metabolism of tumor cells. However, the therapeutic effect of Mito-LND on GBM remains unclear. METHODS: The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism. RESULTS: The results showed that Mito-LND could inhibit the survival, proliferation and colony formation of GBM cells. Moreover, Mito-LND induced cell cycle arrest and apoptosis. Mechanistically, Mito-LND inhibited the activity of mitochondrial respiratory chain complex I and reduced mitochondrial membrane potential, thus promoting ROS generation. Importantly, Mito-LND could inhibit the malignant proliferation of GBM by blocking the Raf/MEK/ERK signaling pathway. In vivo experiments showed that Mito-LND inhibited the growth of GBM xenografts in mice and significantly prolonged the survival time of tumor-bearing mice. CONCLUSION: Taken together, the current findings support that targeting mitochondrial metabolism may be as a potential and promising strategy for GBM therapy, which will lay the theoretical foundation for further clinical trials on Mito-LND in the future.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Animais , Camundongos , Glioblastoma/patologia , Linhagem Celular Tumoral , Transdução de Sinais , Apoptose , Neoplasias Encefálicas/patologia , Proliferação de CélulasRESUMO
BACKGROUND: Clinical outcome of patients with chronic myeloid leukemia (CML) has improved dramatically since the introduction of tyrosine kinase inhibitors such as imatinib mesylate (IM). However, approximately 20-30% of patients experience IM resistance. SH-4-54, which targets the SH2 domains of both proteins STAT3 and STAT5, has been reported to exhibit anticancer activity in solid tumors. However, the roles of SH-4-54 in CML remain unclear. The aim was to explore whether SH-4-54 could overcome IM resistance and identify novel targets for CML. METHODS: Cell viability was measured by CCK-8 assays after treatment of K562 and K562R cells with different concentrations of SH-4-54. Annexin V-FITC and PI were applied to assess the effects of SH-4-54 on cell apoptosis. Effects of SH-4-54 on the expression of proteins downstream of BCR::ABL1 were assessed by western blotting (WB). Effects of SH-4-54 on gene expression profile of CML cells were analyzed by Next generation sequence (NGS). RESULTS: SH-4-54 inhibited the growth of CML cell lines with increasing concentration. SH-4-54 cytotoxic effects correlated with a significant induction of apoptosis. The results of WB analysis showed the downstream proteins of BCR::ABL1, such as STAT3 and STAT5, decreased after SH-4-54 treatment; moreover, the phosphorylation of both proteins were inhibited in dose-dependent manner. Using NGS, we obtained Mrna expression profiles in SH-4-54 treated K562 and K562R cells and identified differentially expressed mRNAs. Among these, STAT3 and STAT5 were markedly downregulated. CONCLUSION: SH-4-54 may overcome IM resistance and represent a promising novel approach to improve the outcome of CML.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Apoptose , Células K562 , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
Reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Although dysregulation of the sole enzyme O-GlcNAc transferase (OGT) was shown to be associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and performs transcriptional functions remain unclear. Here, we demonstrate that elevated OGT levels enhance HCC proliferation and metastasis, in vitro and in vivo, by orchestrating the transcription of numerous regulators of malignancy. Diverse transcriptional regulators are recruited by OGT in HCC cells undergoing malignant progression, which shapes genome-wide OGT chromatin cis-element occupation. Furthermore, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcription in HCC cells. We reveal that O-GlcNAcylation of Ser662 is responsible for the chromatin association of ZNF263 at candidate gene promoters and the OGT-facilitated HCC malignant phenotypes. Our data establish the importance of aberrant OGT activity and ZNF263 O-GlcNAcylation in the malignant progression of HCC and support the investigation of OGT as a therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Cromatina/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , N-Acetilglucosaminiltransferases/genética , Proteínas de Ligação a DNA/genéticaRESUMO
Bortezomib, an FDA approved drug in 2003 for newly diagnosed and relapsed/refractory MM, had showed great efficacy in different clinical settings. However, many patients still developed resistance to Bortezomib, and the mechanism of action remains unelucidated. Here, we showed that Bortezomib resistance can be partially overcome by targeting a different subunit of 20 S complex - PSMB6. PSMB6 knock down by shRNA increased sensitivity to Bortezomib in resistant and sensitive cell line. Interestingly, a STAT3 inhibitor, Stattic, is shown to selectively inhibit PSMB6 and induce apoptosis in Bortezomib resistant and sensitive MM cells, even with IL-6 induction. Therefore, PSMB6 is a novel target for Bortezomib resistance and Stattic may offer a potential therapeutic strategy.
Assuntos
Antineoplásicos , Mieloma Múltiplo , Humanos , Bortezomib/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Apoptose/genética , Linhagem Celular Tumoral , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
DNA topoisomerase IIα (TOP2A) plays a vital role in replication and cell division by catalytically altering DNA topology. It is a prominent target for anticancer drugs, but clinical efficacy is often compromised due to chemoresistance. In this study, we investigate the role of TOP2A O-GlcNAcylation in breast cancer cells and patient tumor tissues. Our results demonstrate that elevated TOP2A, especially its O-GlcNAcylation, promotes breast cancer malignant progression and resistance to adriamycin (Adm). O-GlcNAcylation at Ser1469 enhances TOP2A chromatin DNA binding and catalytic activity, leading to resistance to Adm in breast cancer cells and xenograft models. Mechanistically, O-GlcNAcylation-modulated interactions between TOP2A and cell cycle regulators influence downstream gene expression and contribute to breast cancer drug resistance. These results reveal a previously unrecognized mechanistic role for TOP2A O-GlcNAcylation in breast cancer chemotherapy resistance and provide support for targeting TOP2A O-GlcNAcylation in cancer therapy.
Assuntos
Antineoplásicos , Neoplasias da Mama , Feminino , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos AntineoplásicosRESUMO
Multidrug resistance (MDR) caused by P-glycoprotein (P-gp) is a main barrier to the success of cancer chemotherapies. In this study, fourteen novel dibenzoazepine-tetrahydroisoquinoline hybrids were prepared as potential P-gp inhibitors to surmount MDR caused by P-gp. Amongst them, 8a displayed the most potent inhibition effect on P-gp, thus effectively reversing P-gp-mediated drug resistance with a reversal fold (RF) value of 93.17 in K562/A02 cells. Excitingly, the EC50 value of 8a on MDR reversing effect was 48.74 nM, which was nearly two thousand-fold lower than its IC50 value (95.94 µM) for intrinsic cytotoxicity on K562/A02 cells. Further investigation showed that 8a exerted the MDR reversal effect through impairing P-gp function rather than affecting its expression. Molecular docking and CETSA results illustrated that 8a possessed a relatively high affinity for P-gp, thus effectively improving the stability of P-gp. Furthermore, 8a exhibited a much poorer inhibitory effect on CYP3A4 activity than CYP3A4 inhibitor ketoconazole, thus might not cause unfavorable drug-drug interactions. These data together suggested that 8a may be a promising lead to design P-gp inhibitors, and warranted further investigation on overcoming P-gp-mediated MDR.
Assuntos
Doxorrubicina , Tetra-Hidroisoquinolinas , Humanos , Células K562 , Doxorrubicina/farmacologia , Simulação de Acoplamento Molecular , Resistencia a Medicamentos Antineoplásicos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Tetra-Hidroisoquinolinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismoRESUMO
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with high mortality that urgently requires new treatments. ROCK1 plays an essential role in regulating growth and survival in AML cells. In this study, we evaluated GSK269962A, a selective ROCK1 inhibitor, in preclinical models of AML. Compared with solid tumors, GSK269962A selectively inhibited cell growth and clonogenicity of AML cells. Furthermore, GSK269962A arrested AML cells in the G2 phase and induced apoptosis by regulating multiple cell cycle- and apoptosis-associated proteins. Strikingly, GSK269962A could eliminate leukemia cells from bone marrow, liver, and spleen in an animal model of AML and significantly prolong mouse survival. Mechanistically, GSK269962A could inhibit the growth of AML by blocking ROCK1/c-Raf/ERK signaling pathway. Notably, a correlation was found between the expression levels of ROCK1 protein and the sensitivity of GSK269962A in AML. These data highlight the potential role of ROCK1 as an attractive target for treating AML, as well as the potential of GSK269962A for use in clinical trials of AML.
RESUMO
Activation of antigen-presenting cells (APCs) is crucial in initiating inflammation and alloreaction during acute graft-versus-host disease (aGVHD), a common life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). IL-1 receptor-associated kinase 1 (IRAK1) regulates the activation of APCs in inflammatory settings, and inhibition of IRAK1 might decrease APC activation and aGVHD. This study was conducted to explore the impact of IRAK1 inhibition on APC activation and aGVHD in mice. We administered a selective IRAK1 inhibitor, Jh-X-119-01, to recipient mice undergoing allo-HCT or co-challenged by A20 lymphoma cells. We assessed aGVHD and the graft-versus-lymphoma (GVL) effect. T cell and APC activations were analyzed as well. Jh-X-119-01 was associated with increased survival and decreased aGVHD of recipients. Jh-X-119-01 decreased the proportions of Th1 cells and Tc1 cells in the aGVHD model and in the in vitro mixed lymphocyte reaction. The IRAK1 inhibitor reduced production of TNFα and IFNγ in macrophages of recipient mice. In in vitro cultured bone marrow dendritic cells (BMDCs), Jh-X-119-01 decreased productions of inflammatory cytokines, reduced expression levels of CD80 and CD86, and decreased protein levels of antiapoptotic Bcl2 and phosphorylated NF-κB p65. RNA-seq analysis showed that Jh-X-119-01 had an impact on several pathophysiologic processes of BMDCs, including reduction of GVHD-related genes and regulation of helper T cell differentiation. Importantly, IRAK1 inhibition did not impair cytotoxic function of T cells or the allo-HCT-related GVL effect against A20 lymphoma cells. In addition, the IRAK1 inhibitor did not retard recovery of hematopoietic cells in blood or bone marrow. Our findings show that selective IRAK1 inhibition ameliorates murine aGVHD but preserves the GVL effect. Our findings may have implications for the use of an IRAK1 inhibitor in allo-HCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma , Animais , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Quinases Associadas a Receptores de Interleucina-1/genética , Linfoma/terapia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The NF-κB signaling pathway is an important downstream pathway of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL) cells. However, the molecular mechanisms underlying the cascade activation of Notch1 in T-ALL cells are poorly understood. Here, we evaluated the role of CARMA1 in Notch1-induced NF-κB activation in T-ALL cells. CARMA1 was highly and specifically expressed in T-ALL cells and correlated with the prognosis of T-ALL patients. Interestingly, CARMA1 knockdown only inhibited the growth and proliferation of SIL-TAL1 fusion gene-negative T-ALL cells. In addition, CARMA1 knockdown arrested T-ALL cells at the G1 phase. Furthermore, CARMA1 knockdown significantly inhibited the proliferation of T-ALL cells in vivo and prolonged the survival of mice. Mechanistically, CARMA1 deficiency abolished Notch1-induced NF-κB transcriptional activation and significantly reduced expression levels of the NF-κB target genes c-Myc, Bcl-2, and CCR7. Taken together, these results of our study identify CARMA1 as one of the crucial mediators of Notch1-induced transformation of T-All cells, suggesting that CARMA1 is a promising therapeutic target for T-ALL due to its specific expression in lymphocytes. KEY MESSAGES: CARMA1 contributes to cell survival only in SIL-TAL1 negative T-ALL cells. CARMA1 is a crucial mediator of Notch1-induced activation of NF-κB pathway. CARMA1 is a promising therapeutic target for T-ALL.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Guanilato Ciclase/metabolismo , NF-kappa B/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Células Jurkat , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transdução de Sinais/fisiologia , Proteína 1 de Leucemia Linfocítica Aguda de Células T/metabolismoRESUMO
Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We identified ubiquitin-activating enzyme 1 (UBA1) inhibitor TAK-243 that can strongly induce UPR in GBM cells. In this study, we evaluated the functional activity and mechanism of TAK-243 in preclinical models of GBM. TAK-243 significantly inhibited the survival, proliferation, and colony formation of GBM cell lines and primary GBM cells. It also revealed a significant anti-tumor effect on a GBM PDX animal model and prolonged the survival time of tumor-bearing mice. Notably, TAK-243 more effectively inhibited the survival and self-renewal ability of glioblastoma stem cells (GSCs) than GBM cells. Importantly, we found that the expression level of GRP78 is a key factor in determining the sensitivity of differentiated GBM cells or GSCs to TAK-243. Mechanistically, UBA1 inhibition disrupts global protein ubiquitination in GBM cells, thereby inducing ER stress and UPR. UPR activates the PERK/ATF4 and IRE1α/XBP signaling axes. These findings indicate that UBA1 inhibition could be an attractive strategy that may be potentially used in the treatment of patients with GBM, and GRP78 can be used as a molecular marker for personalized treatment by targeting UBA1.
Assuntos
Apoptose , Neoplasias Encefálicas/patologia , Chaperona BiP do Retículo Endoplasmático/metabolismo , Glioblastoma/patologia , Transdução de Sinais , Enzimas Ativadoras de Ubiquitina/metabolismo , Resposta a Proteínas não Dobradas , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Anotação de Sequência Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteoma/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Sulfonamidas/farmacologia , Ensaio Tumoral de Célula-Tronco , Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Ubiquitinação/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
Glioblastoma multiforme (GBM), a fatal brain tumour with no available targeted therapies, has a poor prognosis. At present, radiotherapy is one of the main methods to treat glioma, but it leads to an obvious increase in inflammatory factors in the tumour microenvironment, especially IL-6 and CXCL1, which plays a role in tumour to resistance radiotherapy and tumorigenesis. Casein kinase 1 alpha 1 (CK1α) (encoded on chromosome 5q by Csnk1a1) is considered an attractive target for Tp53 wild-type acute myeloid leukaemia (AML) treatment. In this study, we evaluated the anti-tumour effect of Csnk1a1 suppression in GBM cells in vitro and in vivo. We found that down-regulation of Csnk1a1 or inhibition by D4476, a Csnk1a1 inhibitor, reduced GBM cell proliferation efficiently in both Tp53 wild-type and Tp53-mutant GBM cells. On the contrary, overexpression of Csnk1a1 promoted cell proliferation and colony formation. Csnk1a1 inhibition improved the sensitivity to radiotherapy. Furthermore, down-regulation of Csnk1a1 reduced the production and secretion of pro-inflammatory factors. In the preclinical GBM model, treatment with D4476 significantly inhibited the increase in pro-inflammatory factors caused by radiotherapy and improved radiotherapy sensitivity, thus inhibiting tumour growth and prolonging animal survival time. These results suggest targeting Csnk1a1 exert an anti-tumour role as an inhibitor of inflammatory factors, providing a new strategy for the treatment of glioma.
Assuntos
Neoplasias Encefálicas/metabolismo , Caseína Quinase Ialfa/metabolismo , Glioma/metabolismo , Tolerância a Radiação , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Caseína Quinase Ialfa/antagonistas & inibidores , Caseína Quinase Ialfa/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Glioma/patologia , Glioma/radioterapia , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteína Supressora de Tumor p53/genéticaRESUMO
Despite advancement in the treatment of diffuse large B-cell lymphoma (DLBCL), many patients tend to relapse or become refractory after initial therapy. Therefore, it is essential to identify novel therapeutic targets and drugs, understand the molecular pathogenesis mechanism of DLBCL, and find ways to prevent and treat relapsed or refractory DLBCL. BIX-01294 is a small molecule compound that specifically inhibits EHMT2 activity. In this study, we demonstrate that BIX-01294 triggered the inhibition of human DLBCL cell proliferation, lead to G1 phase arrest via increasing P21 level and reducing cyclin E level. BIX-01294 also induced apoptosis via endogenous and exogenous apoptotic pathways. Moreover, BIX-01294 triggered autophagy and activated ER stress in human DLBCL cells. Furthermore, we showed that both key components of ER stress, ATF3, and ATF4, are required for BIX-01294-induced apoptosis and autophagy. Hence, this study provides new evidence that EHMT2 may be a new therapeutic target, and BIX-01294 may be a potential therapeutic drug for treating DLBCL.
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Effective treatment for AML is challenging due to the presence of clonal heterogeneity and the evolution of polyclonal drug resistance. Here, we report that TP-0903 has potent activity against protein kinases related to STAT, AKT, and ERK signaling, as well as cell cycle regulators in biochemical and cellular assays. In vitro and in vivo, TP-0903 was active in multiple models of drug-resistant FLT3 mutant AML, including those involving the F691L gatekeeper mutation and bone marrow microenvironment-mediated factors. Furthermore, TP-0903 demonstrated preclinical activity in AML models with FLT3-ITD and common co-occurring mutations in IDH2 and NRAS genes. We also showed that TP-0903 had ex vivo activity in primary AML cells with recurrent mutations including MLL-PTD, ASXL1, SRSF2, and WT1, which are associated with poor prognosis or promote clinical resistance to AML-directed therapies. Our preclinical studies demonstrate that TP-0903 is a multikinase inhibitor with potent activity against multiple drug-resistant models of AML that will have an immediate clinical impact in a heterogeneous disease like AML.
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Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Duplicação Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Camundongos , Camundongos Nus , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Pirimidinas/metabolismo , Sulfonamidas/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Current treatment of T-cell acute lymphoblastic leukemia (T-ALL) is primarily based on high-intensity combination chemotherapy, which has serious side effects. Therefore, developments of novel targeted therapeutics are urgently needed for treatment of T-ALL. In this study, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a novel promising therapeutic target for treatment of T-ALL. MALT1 inhibitor MI-2 significantly suppressed the cell growth, proliferation, and colony formation of T-ALL cells. Furthermore, MI-2 induced cell apoptosis of T-ALL via a mitochondrial-dependent pathway. In a T-ALL mouse model, MI-2 significantly reduced leukemic burden and prolonged the survival of leukemia-bearing mice. Mechanistically, MALT1 inhibition effectively blocked both baseline and Notch1-induced activation of nuclear factor κB pathway, which mediates T-ALL cell survival. In conclusion, our results highlight the potential role of MALT1 as an attractive target for treatment of T-ALL and support the potential of MI-2 or other MALT1 inhibitors to clinical trials in T-ALL.
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Chromosomal region maintenance 1 (CRM1) is associated with an adverse prognosis in glioma. We previously reported that CRM1 inhibition suppressed glioma cell proliferation both in vitro and in vivo. In this study, we investigated the role of CRM1 in the migration and invasion of glioma cells. S109, a novel reversible selective inhibitor of CRM1, was used to treat Human glioma U87 and U251 cells. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. The results showed that S109 significantly inhibited the migration and invasion of U87 and U251 cells. However, mutation of Cys528 in CRM1 abolished the inhibitory activity of S109 in glioma cells. Furthermore, we found that S109 treatment decreased the expression level and activity of MMP2 and reduced the level of phosphorylated STAT3 but not total STAT3. Therefore, the inhibition of migration and invasion induced by S109 may be associated with the downregulation of MMP2 activity and expression, and inactivation of the STAT3 signaling pathway. These results support our previous conclusion that inhibition of CRM1 is an attractive strategy for the treatment of glioma.
RESUMO
Interleukin-1 receptor-associated kinases (IRAKs), particularly IRAK1 and IRAK4, are important in transducing signal from Toll-like receptor 4. We interrogated if a selective inhibition of IRAK1 could alleviate lipopolysaccharide (LPS)-induced sepsis. In this study, we tested the impact of a novel selective IRAK1 inhibitor Jh-X-119-01 on LPS-induced sepsis in mice. Survival at day 5 was 13.3% in control group where septic mice were treated by vehicle, while the values were 37.5% (p = 0.046, vs. control) and 56.3% (p = 0.003, vs. control) for 5 mg/kg and 10 mg/kg Jh-X-119-01-treated mice. Jh-X-119-01 alleviated lung injury and reduced production of TNFα and IFNγ in peritoneal macrophages. Jh-X-119-01 decreased phosphorylation of NF-κB and mRNA levels of IL-6 and TNFα in LPS-treated macrophages in vitro. Jh-X-119-01 selectively inhibited IRAK1 phosphorylation comparing with a non-selective IRAK1/4 inhibitor which simultaneously inhibited phosphorylation of IRAK1 and IRAK4. Both Jh-X-119-01 and IRAK1/4 inhibitor increased survival of septic mice, but Jh-X-119-01-treated mice had higher blood CD11b+ cell counts than IRAK1/4 inhibitor-treated ones [24 h: (1.18 ± 0.26) × 106/ml vs. (0.79 ± 0.20) × 106/ml, p = 0.001; 48 h: (1.00 ± 0.30) × 106/ml vs. (0.67 ± 0.23) × 106/ml, p = 0.042]. IRAK1/4 inhibitor induced more apoptosis of macrophages than Jh-X-119-01 did in vitro. IRAK1/4 inhibitor decreased protein levels of anti-apoptotic BCL-2 and MCL-1 in RAW 264.7 and THP-1 cells, an effect not seen in Jh-X-119-01-treated cells. In conclusion, Jh-X-119-01 selectively inhibited activation of IRAK1 and protected mice from LPS-induced sepsis. Jh-X-119-01 showed less toxicity on macrophages comparing with a non-selective IRAK1/4 inhibitor.