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1.
Cancer Res Commun ; 4(6): 1441-1453, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38727208

RESUMEN

Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion of and resistance to apoptosis are significant factors in tumorigenesis and drug resistance. Bypassing apoptotic pathways and eliciting another form of regulated cell death, namely necroptosis, an immunogenic cell death (ICD), may override apoptotic resistance. Here, we present the mechanistic rationale for combining tolinapant, an antagonist of the inhibitor of apoptosis proteins (IAP), with decitabine, a hypomethylating agent (HMA), in T-cell lymphoma (TCL). Tolinapant treatment alone of TCL cells in vitro and in syngeneic in vivo models demonstrated that ICD markers can be upregulated, and we have shown that epigenetic priming with decitabine further enhances this effect. The clinical relevance of ICD markers was confirmed by the direct measurement of plasma proteins from patients with peripheral TCL treated with tolinapant. We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in IFN signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation. SIGNIFICANCE: The IAP antagonist tolinapant can induce necroptosis, a key immune-activating event, in TCL. Combination with DNA hypomethylation enhances tolinapant sensitivity and primes resistant cells by re-expressing necrosome proteins. In addition, this combination leads to increases in genes involved in IFN signaling and neoantigen expression, providing further molecular rationale for this novel therapeutic option.


Asunto(s)
Metilación de ADN , Decitabina , Epigénesis Genética , Linfoma de Células T , Humanos , Epigénesis Genética/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Animales , Decitabina/farmacología , Decitabina/uso terapéutico , Ratones , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/inmunología , Linfoma de Células T/genética , Linfoma de Células T/patología , Línea Celular Tumoral , Necroptosis/efectos de los fármacos , Apoptosis/efectos de los fármacos
2.
Cell Death Differ ; 27(6): 1878-1895, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31831875

RESUMEN

Therapeutic efficacy of first-generation hypomethylating agents (HMAs) is limited in elderly acute myeloid leukemia (AML) patients. Therefore, combination strategies with targeted therapies are urgently needed. Here, we discover that priming with SGI-110 (guadecitabine), a next-generation HMA, sensitizes AML cells to ASTX660, a novel antagonist of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked IAP (XIAP). Importantly, SGI-110 and ASTX660 synergistically induced cell death in a panel of AML cell lines as well as in primary AML samples while largely sparing normal CD34+ human progenitor cells, underlining the translational relevance of this combination. Unbiased transcriptome analysis revealed that SGI-110 alone or in combination with ASTX660 upregulated the expression of key regulators of both extrinsic and intrinsic apoptosis signaling pathways such as TNFRSF10B (DR5), FAS, and BAX. Individual knockdown of the death receptors TNFR1, DR5, and FAS significantly reduced SGI-110/ASTX660-mediated cell death, whereas blocking antibodies for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or FAS ligand (FASLG) failed to provide protection. Also, TNFα-blocking antibody Enbrel had little protective effect on SGI-110/ASTX660-induced cell death. Further, SGI-110 and ASTX660 acted in concert to promote cleavage of caspase-8 and BID, thereby providing a link between extrinsic and intrinsic apoptotic pathways. Consistently, sequential treatment with SGI-110 and ASTX660-triggered loss of mitochondrial membrane potential (MMP) and BAX activation which contributes to cell death, as BAX silencing significantly protected from SGI-110/ASTX660-mediated apoptosis. Together, these events culminated in the activation of caspases-3/-7, nuclear fragmentation, and cell death. In conclusion, SGI-110 and ASTX660 cooperatively induced apoptosis in AML cells by engaging extrinsic and intrinsic apoptosis pathways, highlighting the therapeutic potential of this combination for AML.


Asunto(s)
Apoptosis/efectos de los fármacos , Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Morfolinas/farmacología , Piperazinas/farmacología , Pirroles/farmacología , Anciano , Azacitidina/farmacología , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/antagonistas & inhibidores , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores
3.
Mol Cancer Ther ; 17(7): 1381-1391, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29695633

RESUMEN

Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell lines in vitro, whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I-II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1381-91. ©2018 AACR.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Proteínas Inhibidoras de la Apoptosis/química , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Imitación Molecular , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Relación Estructura-Actividad , Proteína Inhibidora de la Apoptosis Ligada a X/química , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Med Chem ; 61(16): 7314-7329, 2018 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-30091600

RESUMEN

Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP-XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate 27 (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423).


Asunto(s)
Antineoplásicos/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Piperazinas/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Canal de Potasio ERG1/antagonistas & inhibidores , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Macaca fascicularis , Masculino , Ratones Endogámicos BALB C , Piperazinas/química , Piperazinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Proteína Inhibidora de la Apoptosis Ligada a X/química , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
J Med Chem ; 60(11): 4611-4625, 2017 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-28492317

RESUMEN

XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies, and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.


Asunto(s)
Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Piperazinas/química , Piperazinas/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Cristalografía por Rayos X , Descubrimiento de Drogas , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Peptidomiméticos , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad
6.
Oncotarget ; 7(7): 7885-98, 2016 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-26799286

RESUMEN

PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy.


Asunto(s)
Quimioradioterapia , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Macrófagos/patología , Fosfohidrolasa PTEN/metabolismo , Neoplasias de la Próstata/radioterapia , Fármacos Sensibilizantes a Radiaciones/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Western Blotting , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Quimiotaxis/efectos de la radiación , Metilación de ADN/efectos de los fármacos , Metilación de ADN/efectos de la radiación , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Proteínas Inhibidoras de la Apoptosis/efectos de los fármacos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Interleucina-8/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/efectos de la radiación , Masculino , Clasificación del Tumor , Pronóstico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Rayos X
7.
J Med Chem ; 58(16): 6574-88, 2015 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-26218264

RESUMEN

Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis and pro-survival signaling pathways whose deregulation is often associated with tumor genesis and tumor growth. IAPs have been proposed as targets for anticancer therapy, and a number of peptidomimetic IAP antagonists have entered clinical trials. Using our fragment-based screening approach, we identified nonpeptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based hit optimization together with an analysis of protein-ligand electrostatic potential complementarity allowed us to significantly increase binding affinity of the starting hits. Subsequent optimization gave a potent nonalanine IAP antagonist structurally distinct from all IAP antagonists previously reported. The lead compound had activity in cell-based assays and in a mouse xenograft efficacy model and represents a highly promising start point for further optimization.


Asunto(s)
Antineoplásicos/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Inhibidoras de la Apoptosis/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Proliferación Celular/efectos de los fármacos , Biología Computacional , Diseño de Fármacos , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/farmacocinética , Piperazinas/síntesis química , Piperazinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
8.
J Immunol ; 177(2): 885-95, 2006 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-16818743

RESUMEN

The key interaction in the adaptive immune system's response to pathogenic challenge occurs at the interface between APCs and T cells. Families of costimulatory and coinhibitory molecules function in association with the cytokine microenvironment to orchestrate appropriate T cell activation programs. Recent data have demonstrated that the Notch receptor and its ligands also function at the APC:T interface. In this study, we describe synthetic small interfering RNA (siRNA) sequences targeting the human Notch ligands Delta1, Jagged1 and Jagged2. Transfection of these siRNAs into human primary CD4(+) T cells and monocyte-derived dendritic cells leads to knockdown of endogenous Notch ligand message. Knockdown of any one of these three Notch ligands in dendritic cells enhanced IFN-gamma production from allogeneic CD4(+) T cells in MLR. In contrast, Delta1 knockdown in CD4(+) T cells selectively enhanced production of IFN-gamma, IL-2, and IL-5 in response to polyclonal stimulation, while Jagged1 or Jagged2 knockdown had no effect. Strikingly, blockade of Notch cleavage with a gamma secretase inhibitor failed to affect cytokine production in this system, implying that Delta1 can influence cytokine production via a Notch cleavage-independent mechanism. These data show for the first time that the Notch pathway can be targeted by siRNA, and that its antagonism may be a unique therapeutic opportunity for immune enhancement.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/biosíntesis , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , ARN Interferente Pequeño/genética , Receptores Notch/antagonistas & inhibidores , Receptores Notch/genética , Animales , Células CHO , Proteínas de Unión al Calcio/antagonistas & inhibidores , Proteínas de Unión al Calcio/biosíntesis , Proteínas de Unión al Calcio/genética , Células Cultivadas , Cricetinae , Citocinas/antagonistas & inhibidores , Humanos , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intracelular , Proteína Jagged-1 , Proteína Jagged-2 , Ligandos , Prueba de Cultivo Mixto de Linfocitos , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Proteínas de la Membrana/farmacología , Receptores Notch/metabolismo , Proteínas Recombinantes/farmacología , Proteínas Serrate-Jagged , Transducción de Señal/genética , Transducción de Señal/inmunología , Transfección , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología
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