RESUMEN
PURPOSE: A phase II study was conducted to evaluate the safety and efficacy of the combination of HER2 bispecific antibody (HER2Bi)-armed activated T cells (HER2 BAT) and programmed death 1 inhibitor, pembrolizumab. PATIENTS AND METHODS: Patients with metastatic castration-resistant prostate cancer (mCRPC) with 0 to 1 performance status and normal liver, kidney, and marrow function, pre- or post-docetaxel chemotherapy were eligible. Primary endpoint was 6-month progression-free survival (PFS). Peripheral blood mononuclear cells were obtained by a single apheresis, shipped to University of Virginia, activated with OKT3 and expanded for 14 days in IL2, harvested, and armed with HER2Bi and cryopreserved. HER2 BATs were infused twice weekly for 4 weeks and pembrolizumab was administered every 21 days for a maximum duration of 6 months starting 1 to 3 weeks prior to HER2 BATs infusion. RESULTS: Fourteen patients were enrolled with a median age of 69 (range 57-82 years) and median PSA of 143.4 (range 8.2-4210 ng/dL). Two patients had peritoneal metastases, 1 had lymph node (LN) only metastases and 11 had bone metastases of which 7 had bone and LN metastases. All were pretreated with androgen receptor axis targeted agents and 7 (50%) had prior docetaxel chemotherapy. The toxicities were grade1-2 infusion reactions with fever, chills, headaches, nausea and/or myalgias. Primary endpoint of 6 month PFS was achieved in 5 of 14 patients (38.5%; 95% confidence interval, 19.5%-76.5%). Median PFS was 5 months and median survival was 31.6 months. CONCLUSIONS: The safety and promising efficacy makes this combination worthy of future investigation in mCRPC.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Docetaxel/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Leucocitos Mononucleares , Linfocitos T , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706.
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Antagonistas de Andrógenos/uso terapéutico , Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Negro o Afroamericano , Nitrilos/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Compuestos de Tosilo/uso terapéutico , Anciano , Anciano de 80 o más Años , Benzamidas , Biomarcadores de Tumor/sangre , Quimioterapia Combinada , Humanos , Masculino , Persona de Mediana Edad , Feniltiohidantoína/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/etnología , Resultado del TratamientoRESUMEN
PURPOSE: Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib.Experimental Design: Eligibility included patients with metastatic castrate-resistant prostate cancer with normal organ function and performance status 0-2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans, positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl) thymine (FMAU PET) scans were conducted. Pretherapy and posttherapy tumor biopsies were conducted, and serum and urine bone markers were measured. RESULTS: Twenty evaluable patients were treated. Eight patients had a PSA decline, of which 2 had a decline of ≥50%. Median progression-free survival (PFS) and OS were 4.1 and 11.2 months, respectively, and 3 patients were on therapy for 8, 10, and 13 months. The NaF-PET demonstrated a median decline in SUVmax of -56% (range, -85 to -5%, n = 11) and -41% (range, -60 to -25%, n = 9) for patients who were clinically stable and remained on therapy for ≥4 or <4 cycles, respectively. The FMAU PET demonstrated a median decline in SUVmax of -44% (-60 to -14%) and -42% (-63% to -23%) for these groups. The changes in bone markers and mesenchymal epithelial transition/MET testing did not correlate with clinical benefit. CONCLUSIONS: Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.
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Biomarcadores de Tumor , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Huesos/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Anilidas/administración & dosificación , Biopsia , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/mortalidad , Huesos/patología , Manejo de la Enfermedad , Humanos , Procesamiento de Imagen Asistido por Computador , Calicreínas/sangre , Masculino , Persona de Mediana Edad , Modelos Biológicos , Terapia Molecular Dirigida , Tomografía de Emisión de Positrones , Pronóstico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Resultado del TratamientoRESUMEN
Aberrant regulation of microRNA expression in pancreatic cancers has been shown to play an important role in its inherent poor prognosis and malignant potential. MicroRNAs have also been shown to inhibit translation of genes by targeting the 3'-untranslated region (3-UTR) of mRNAs resulting in the inhibition of translation and often destruction of the mRNA. In the present study we investigated the role of the microRNA miR-202 in the apoptotic pathways of pancreatic cancer cells. The adamantyl-related molecule, 3-Cl-AHPC down-regulated expression of miR-202 and miR-578 resulting in the increased expression of mRNA and protein expression of their target genes, Max dimerization protein 1 (Mxd1/Mad1) and the Sin3A associated protein 18 (SAP18). Overexpression of pre-miR-202 led to diminished levels of Mxd1 and blocked the 3-Cl-AHPC-mediated increase in Mxd1 mRNA expression. The addition of the microRNA inhibitor 2'-O-methylated miR-202 enhanced the 3-Cl-AHPC-mediated increase of Mxd1 mRNA levels as well as 3-CI-AHPC-mediated apoptosis. We found increased Mxd1 bound to the Sin3A repressor protein complex through its increased binding with HDAC-2 and subsequently enhanced transcriptional repression in cells as evidenced by increased HDAC activity. Mxd1 also repressed human telomerase reverse transcriptase (hTERT) mRNA expression through its increased binding to the hTERT promoter site and resulted in decreased telomerase activity in cells. Our results demonstrate that down regulation of miR-202 increased the expression of its target Mxd1, followed by Mxd1 recruitment to the Sin3A repressor complex and through its dimerization with Max, and increased repression of Myc-Max target proteins.
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Apoptosis/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias Pancreáticas/genética , Proteínas Represoras/genética , Regiones no Traducidas 3' , Adamantano/análogos & derivados , Adamantano/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cinamatos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Unión Proteica , Interferencia de ARN , Complejo Correpresor Histona Desacetilasa y Sin3 , Telomerasa/genética , Telomerasa/metabolismoRESUMEN
Transcription factor NF-κB promotes cell proliferation in response to cell injury. Increasing evidence, however, suggests that NF-κB can also play an apoptotic role depending on the stimulus and cell type. We have previously demonstrated that novel retinoid 4-[3-Cl-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated apoptosis in breast carcinoma cells requires activation of canonical and non-canonical NF-κB pathways. The mechanism NF-κB uses to induce apoptosis remains largely unknown. NF-κB subunit p65 (RelA) was identified as one potent transcriptional activator in 3-Cl-AHPC-mediated apoptosis in cells. Here we used ChIP-on-chip to identify NF-κB p65 genes activated in 3-Cl-AHPC mediated apoptosis. This paper focuses on one hit: pro-apoptotic protein programmed cell death 5 (PDCD5). 3-Cl-AHPC mediated apoptosis in MDA-MB-468 had three related effects on PDCD5: NF-κB p65 binding to the PDCD5 gene, enhanced PDCD5 promoter activity, and increased PDCD5 protein expression. Furthermore, 3-Cl-AHPC increased orphan nuclear receptor small heterodimer partner (SHP) mRNA expression, increased SHP protein bound to NF-κB p65, and found the SHP/NF-κB p65 complex attached to the PDCD5 gene. PDCD5 triggered apoptosis through increased Bax protein and release of cytochrome C from mitochondria to cytosol. Lastly, knockdown of PDCD5 protein expression blocked 3-Cl-AHPC mediated apoptosis, while over-expression of PDCD5 enhanced apoptosis, suggesting PDCD5 is necessary and sufficient for NF-κB p65 mediated apoptosis. Our results demonstrate a novel pathway for NF-κB p65 in regulating apoptosis through SHP and PDCD5.
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Adamantano/análogos & derivados , Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis , Cinamatos/farmacología , Proteínas de Neoplasias/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factor de Transcripción ReIA/metabolismo , Adamantano/farmacología , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Humanos , Proteínas de Neoplasias/genética , Receptores Citoplasmáticos y Nucleares/genética , Factor de Transcripción ReIA/genéticaRESUMEN
MicroRNAs have been implicated in many critical cellular processes including apoptosis. We have previously found that apoptosis in pancreatic cancer cells was induced by adamantyl retinoid-related (ARR) molecule 3-Cl-AHPC. Here we report that 3-Cl-AHPC-dependent apoptosis involves regulating a number of microRNAs including miR-150* and miR-630. 3-Cl-AHPC stimulated miR-150* expression and caused decreased expression of c-Myb and IGF-1R in the pancreatic cancer cells. 3-Cl-AHPC-mediated reduction of c-Myb resulted in diminished binding of c-Myb with IGF-1R and Bcl-2 promoters, thereby causing repression of their transcription and protein expression. Over-expression of miR-150* also resulted in diminished levels of c-Myb and Bcl-2 proteins. Furthermore, the addition of the miRNA inhibitor 2'-O-methylated miR-150 blocked 3-Cl-AHPC-mediated increase in miR-150* levels and abrogated loss of c-Myb protein. Knockdown of c-Myb in PANC-1 cells resulted in enhanced apoptosis both in the presence or absence of 3-Cl-AHPC confirming the anti-apoptotic property of c-Myb. Overexpression of miR-630 also induced apoptosis in the pancreatic cancer cells and inhibited target protein IGF-1R mRNA and protein expression. Together these results implicate key roles for miR-150* and miR-630 and their targeting of IGF-1R to promote apoptosis in pancreatic cancer cells.
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Apoptosis/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias Pancreáticas/genética , Receptor IGF Tipo 1/genética , Adamantano/análogos & derivados , Adamantano/farmacología , Antígeno CD24/metabolismo , Línea Celular Tumoral , Cinamatos/farmacología , Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Genes bcl-2 , Humanos , Receptores de Hialuranos/metabolismo , MicroARNs/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias Pancreáticas/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Proto-Oncogénicas c-myb/genética , Proteínas Proto-Oncogénicas c-myb/metabolismo , Receptor IGF Tipo 1/metabolismo , Esferoides Celulares , Células Tumorales CultivadasRESUMEN
Pancreatic carcinoma has a dismal prognosis as it often presents as locally advanced or metastatic. We have found that exposure to adamantyl-substituted retinoid-related (ARR) compounds 3-Cl-AHPC and AHP3 resulted in growth inhibition and apoptosis induction in PANC-1, Capan-2, and MiaPaCa-2 pancreatic cancer cell lines. In addition, AHP3 and 3-Cl-AHPC inhibited growth and induced apoptosis in spheres derived from the CD44(+)/CD24(+) (CD133(+)/EpCAM(+)) stem-like cell population isolated from the pancreatic cancer cell lines. 3-Cl-AHPC-induced apoptosis was preceded by decreasing expression of IGF-1R, cyclin D1, ß-catenin, and activated Notch-1 in the pancreatic cancer cell lines. Decreased IGF-1R expression inhibited PANC-1 proliferation, enhanced 3-Cl-AHPC-mediated apoptosis, and significantly decreased sphere formation. 3-Cl-AHPC inhibited the Wnt/ß-catenin pathway as indicated by decreased ß-catenin nuclear localization and inhibited Wnt/ß-catenin activation of transcription factor TCF/LEF. Knockdown of ß-catenin using sh-RNA also induced apoptosis and inhibited growth in pancreatic cancer cells. Thus, 3-Cl-AHPC and AHP3 induce apoptosis in pancreatic cancer cells and cancer stem-like cells and may serve as an important potential therapeutic agent in the treatment of pancreatic cancer.
RESUMEN
The parent phenol of adapalene and its (E)-cinnamic acid analogue were found to induce cancer cell apoptosis but cause adverse systemic effects when administered to mice. In contrast, their respective 5-Cl- and 3-Cl-substituted analogues had their adverse effects mitigated without a comparable loss of cancer cell inhibitory activity. As a result, pharmacologic space in this region of the cinnamic phenyl ring scaffold was explored. Various substituents were introduced, and their effects on cancer cell proliferation and viability were evaluated. Cinnamic acids having 3-Br, CN, NO(2), NH(2), OMe, and N(3) groups had activity comparable to that of 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid. A comparative molecular field analysis study indicated that introduction of an H-bond acceptor at position 3 of the central phenyl ring would favor inhibition of leukemia cell viability, and docking suggested its hydrogen bonding with a polar group in a small heterodimer partner homology model. The 3-CN, NO(2), NH(2), and OH analogues also inhibited MMTV-Wnt1 murine mammary stem cell viability.
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Adamantano/análogos & derivados , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Cinamatos/síntesis química , Receptores Citoplasmáticos y Nucleares/metabolismo , Adamantano/síntesis química , Adamantano/química , Adamantano/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cinamatos/química , Cinamatos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Leucemia , Ligandos , Ratones , Modelos Moleculares , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre/citología , Células Madre/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Proteína Wnt1/metabolismoRESUMEN
(E)-4-[3'-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell cycle arrest and apoptosis of cancer cells. Because its pharmacologic properties-solubility, bioavailability, and toxicity-required improvement for translation, structural modifications were made by introducing nitrogen atoms into the cinnamyl ring and replacing its E-double bond with XCH(2) (X = O, N, and S) with the objective of enhancing these properties without impacting apoptosis-inducing activity. Analogues having nitrogen atoms in heterocyclic rings corresponding to the cinnamyl phenyl ring displayed equal or higher biological activities. The pyrimidine and pyridine analogues were more soluble in both phosphate-buffered saline and water. While the 2,5-disubstituted pyridine analogue was the most potent inducer of KG-1 acute myeloid leukemia cell apoptosis, on the basis of apoptotic activity in KG-1 cells and solubility, the 2,5-disubstituted pyrimidine proved to be the more promising candidate for treatment of acute myeloid leukemia.
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Acrilatos/síntesis química , Acrilatos/farmacología , Adamantano/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Cinamatos/química , Leucemia Mieloide Aguda/tratamiento farmacológico , Receptores Nucleares Huérfanos/metabolismo , Acrilatos/química , Acrilatos/metabolismo , Adamantano/síntesis química , Adamantano/química , Adamantano/metabolismo , Adamantano/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Cinamatos/farmacología , Diseño de Fármacos , Humanos , Ligandos , RatonesRESUMEN
The adamantyl-substituted retinoid-related (ARR) compounds 3-Cl-AHPC and AHP3 induce apoptosis in vitro and in vivo in a newly established human acute myelogenous leukemia (AML) cell line, FFMA-AML, and in the established TF(v-SRC) AML cell line. FFMA-AML and TF(v-SRC) cells displayed resistance to apoptosis mediated by the standard retinoids (including trans-retinoic acid, 9-cis-retinoic acid, and the synthetic retinoid TTNPB) but showed sensitivity to apoptosis mediated by 3-Cl-AHPC- and AHP3 in vitro and in vivo as documented by poly(ADP-ribose) polymerase (PARP) cleavage and apoptosis terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. 3-Cl-AHPC or AHP3 exposure in vitro resulted in decreased expression of the antiapoptotic proteins (cellular inhibitor of apoptosis 1, X-linked inhibitor of apoptosis protein) and phospho-Bad and activated the NF-κB canonical pathway. A significant prolongation of survival was observed both in nonobese diabetic severe combined immunodeficient mice carrying FFMA-AML cells and treated with either 3-Cl-AHPC or AHP3 and in severe combined immunodeficient mice carrying TF(v-SRC) cells and treated with AHP3. We have previously shown that ARRs bind to the orphan nuclear receptor small heterodimer partner (SHP) and that the expression of SHP is required for ARR-mediated apoptosis. Induced loss of SHP in these AML cells blocked 3-Cl-AHPC- and AHP3-mediated induction of apoptosis. These results support the further development of 3-Cl-AHPC and AHP3 as potential therapeutic agents in the treatment of AML patients.
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Adamantano/análogos & derivados , Apoptosis/efectos de los fármacos , Leucemia Mieloide Aguda/patología , Retinoides/química , Retinoides/farmacología , Acrilatos/química , Acrilatos/farmacología , Adamantano/química , Adamantano/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Cinamatos/química , Cinamatos/farmacología , Humanos , Ratones , Ratones Endogámicos ICR , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: A variety of pathways target CDKI p21WAF1/CIP1 expression at transcriptional, post-transcriptional as well as translational levels. We previously found that cell growth suppressing retinoid CD437 enhanced expression of p21WAF1/CIP1 and DNA damage inducible GADD45 proteins in part by elevating their mRNA stability. RESULTS: Here, we investigated molecular mechanisms of CD437-dependent post-transcriptional regulation of p21WAF1/CIP1 expression. By utilizing MDA-MB-468 HBC cells expressing chimeric rabbit beta-globin-p21WAF1/CIP1 transcripts we mapped multiple CD437-responsive sequences located within positions 1195 to 1795 of the 3'-untranslated region of p21WAF1/CIP1 mRNA. Several cytoplasmic proteins present in MDA-MB-468, MCF-7 HBC as well as HL-60R leukemia cells bound specifically, in vitro, with these CD437-responsive sequences. CD437 treatment of cells resulted in elevated binding of ~85 kD and ~55 kD cytoplasmic proteins with putative CD437-responsive sequences. A 12 nt RNA sequence (5'-UGUGGUGGCACA-3') present within CD437-responsive region of p21WAF1/CIP1 mRNA displayed specific and elevated binding with the above noted proteins. Treatment of cells with ActD or CHX prior to CD437 exposure did not abrogate RNA-protein interactions. However, treatment of cytoplasmic protein extracts with proteinase K or alkaline phosphatase resulted in loss of RNA-protein interactions. CONCLUSIONS: CD437 regulates cell growth in part by regulating stability of p21WAF1/CIP1 mRNA that involves specific RNA-protein interactions that are phosphorylation-dependent, while not requiring nascent transcription or protein synthesis.
RESUMEN
BACKGROUND: CARP-1/CCAR1, a perinuclear phospho-protein, regulates signaling by adriamycin, steroids, or growth factors. However, intracellular events that regulate CARP-1-dependent cell growth are not fully understood. RESULTS: Here we investigated whether CARP-1 is involved in signaling induced by the protein kinase A inhibitor H89. Treatments of human breast cancer cells with H89 resulted in apoptosis that involved enhanced CARP-1 threonine phosphorylation and expression. Depletion of CARP-1, on the other hand, abrogates apoptosis induced by H89. CARP-1 binds with signal transducer TAZ and over-expression of TAZ inhibits apoptosis by CARP-1. CARP-1 (651-759) interacts with a novel, N-terminal epitope of TAZ. H89 treatment stimulates threonine phosphorylation of CARP-1 (651-759), while substitution of threonine667 to alanine interferes with its binding with TAZ and apoptosis by H89. In addition, expression of wild type or CARP-1 (651-759) causes loss of c-myc expression due, in part, to suppression of c-myc transcription. CONCLUSIONS: CARP-1 threonine667 regulates H89-dependent signaling by a novel pathway that involves modulation of CARP-1 interaction with TAZ and transcriptional down-regulation of c-myc.
RESUMEN
Increasing evidence demonstrates that three classes of molecules originally derived from all-trans-retinoic acid and its synthetic analogues, which function by interacting with the retinoid nuclear receptors, exert their anticancer activities through alternative signaling pathways. Thus, the methylene-linked analogues (4-HBR, 4-HPRCG, and 4-HBRCG) of N-(4-hydroxyphenyl) retinamide (4-HPR) and its O-glucuronide metabolite (4-HPROG), the cinnamic acid analogues (3-Cl-AHPC and AHPC/ST1926) of 6-[3'-(1-adamantyl)-4'-hydroxyphenyl)]-2-naphthalenecarboxylic acid, and N-(2,3-dihydro-2,2,4,4-tetramethyl-6-benzothiopyranyl),N'-(4-nitrophenyl)thiourea (SHetA2) induce cancer cell-cycle arrest and apoptosis mediated most likely through mitochondrial and/or endoplasmic reticulum stress responses. Structure-activity relationships and potential for clinical translation as anticancer therapeutics are presented.
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Antineoplásicos/química , Receptores de Ácido Retinoico/metabolismo , Retinoides/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis , Cinamatos/síntesis química , Cinamatos/química , Cinamatos/farmacología , Fenretinida/análogos & derivados , Fenretinida/síntesis química , Fenretinida/química , Fenretinida/farmacología , Glucuronatos/síntesis química , Glucuronatos/química , Glucuronatos/farmacología , Receptores de Ácido Retinoico/química , Retinoides/síntesis química , Retinoides/farmacología , Relación Estructura-ActividadRESUMEN
We previously found that the adamantyl-substituted retinoid-related molecules bind to the small heterodimer partner (SHP) as well as the Sin3A complex. In this report, we delineated the role of SHP and the Sin3A complex in 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated inhibition of cell growth and apoptosis. We examined the effect of loss of SHP and Sin3A expression in a number of cell types on 3-Cl-AHPC-mediated growth inhibition and apoptosis induction, 3-Cl-AHPC-mediated nuclear factor-kappaB (NF-kappaB) activation, and 3-Cl-AHPC-mediated increase in c-Fos and c-Jun expression. We found that loss of SHP or Sin3A expression, while blocking 3-Cl-AHPC-mediated apoptosis, had little effect on 3-Cl-AHPC inhibition of cellular proliferation. We have previously shown that 3-Cl-AHPC-mediated NF-kappaB activation is necessary for apoptosis induction. We have now shown that 3-Cl-AHPC-enhanced c-Fos and c-Jun expression is also essential for maximal 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC induction of c-Fos and c-Jun expression as well as NF-kappaB activation was dependent on SHP protein levels. In turn, SHP levels are regulated by Sin3A because ablation of Sin3A resulted in a decrease in SHP expression. Thus, SHP and Sin3A play an important role in adamantyl-substituted retinoid-related induction of cellular apoptosis.
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Adamantano/análogos & derivados , Apoptosis/efectos de los fármacos , Cinamatos/farmacología , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Represoras/metabolismo , Adamantano/farmacología , Animales , Western Blotting , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inmunoprecipitación de Cromatina , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Histona Desacetilasas/metabolismo , Humanos , Unión Proteica , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Interferente Pequeño/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Complejo Correpresor Histona Desacetilasa y Sin3 , TransfecciónRESUMEN
PPARgamma agonist DIM-Ph-4-CF(3), a template for RXRalpha agonist (E)-3-[5-di(1-methyl-1H-indol-3-yl)methyl-2-thienyl] acrylic acid: DIM-Ph-CF(3) is reported to inhibit cancer growth independent of PPARgamma and to interact with NR4A1. As both receptors dimerize with RXR, and natural PPARgamma ligands activate RXR, DIM-Ph-4-CF(3) was investigated as an RXR ligand. It displaces 9-cis-retinoic acid from RXRalpha but does not activate RXRalpha. Structure-based direct design led to an RXRalpha agonist.1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene (DIM-Ph-4-CF(3)) is reported to inhibit cancer cell growth and to act as a transcriptional agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear receptor 4A subfamily member 1 (NR4A1). In addition, DIM-Ph-4-CF(3) exerts anticancer effects independent of these receptors because PPARgamma antagonists do not block its inhibition of cell growth, and the small pocket in the NR4A1 crystal structure suggests no ligand can bind. Because PPARgamma and NR4A1 heterodimerize with retinoid X receptor (RXR), and several PPARgamma ligands transcriptionally activate RXR, DIM-Ph-4-CF(3) was investigated as an RXR ligand. DIM-Ph-4-CF(3) displaces 9-cis-retinoic acid from RXRalpha but does not transactivate RXRalpha. Structure-based design using DIM-Ph-4-CF(3) as a template led to the RXRalpha transcriptional agonist (E)-3-[5-di(1-methyl-1H-indol-3-yl)methyl-2-thienyl]acrylic acid. Its docked pose in the RXRalpha ligand binding domain suggests that binding is stabilized by interactions of its carboxylate group with arginine 316, its indoles with cysteines 269 and 432, and its 1-methyl groups with hydrophobic residues lining the binding pocket. As is expected of a selective activator of RXRalpha, but not of RARs and PPARgamma, this RXRalpha agonist, unlike DIM-Ph-4-CF(3), does not appreciably decrease cancer cell growth or induce apoptosis at pharmacologically relevant concentrations.
Asunto(s)
Fluorobencenos/química , PPAR gamma/metabolismo , Receptores X Retinoide/metabolismo , Sitios de Unión , Unión Competitiva , Línea Celular Tumoral , Simulación por Computador , Proteínas de Unión al ADN/metabolismo , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Fluorobencenos/síntesis química , Fluorobencenos/farmacología , Humanos , Ligandos , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , PPAR gamma/agonistas , Receptores de Esteroides/metabolismo , Receptores X Retinoide/agonistasRESUMEN
OBJECTIVE: To report a case of probable trastuzumab-induced hepatotoxicity. CASE SUMMARY: A 54-year-old African American woman presented with locally advanced right-sided breast cancer that was found to be strongly positive for human epidermal growth factor receptor 2 (HER2) by fluorescence in situ hybridization. She was treated with neoadjuvant chemotherapy with 4 cycles of dose-dense doxorubicin and cyclophosphamide. Laboratory test results, including liver function tests (LFTs), were normal at that time. Therapy consisting of weekly doses of paclitaxel 80 mg/m(2) and a loading dose of trastuzumab 4 mg/kg for the first week and 2 mg/kg weekly thereafter was started. Alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels began to increase after the initial dose; the levels were significantly elevated after the fifth cycle. Paclitaxel was withheld, and trastuzumab was continued, as there were no prior reported cases of trastuzumab-induced hepatotoxicity at that time. Other possible etiologies for the elevated enzyme levels, including metastasis to the liver, were excluded. The patient continued to receive trastuzumab for a total of 8 weeks; it was discontinued at that time because enzyme levels continued to increase. When trastuzumab was discontinued, enzyme levels returned to normal. Subsequently, surgical resection of the cancer was performed. The patient's lymph nodes were found to be involved and, because of the high risk of disease recurrence, she was rechallenged with trastuzumab. LFTs showed enzyme levels rising again and trastuzumab was discontinued after 2 cycles, with subsequent normalization of the levels. She was then treated with weekly paclitaxel and her LFT values continued to be in the near-normal range. DISCUSSION: There were no comorbidities in this patient and, on initiation of trastuzumab, her liver enzyme levels were normal. The levels became elevated after initiation of trastuzumab, normalized after its discontinuation, and increased upon rechallenge. According to a validated drug-induced hepatotoxicity scale, trastuzumab was the probable cause of hepatotoxicity in this patient. CONCLUSIONS: Liver enzyme levels must be closely monitored in patients receiving trastuzumab. To our knowledge, this is the first report of trastuzumab-induced hepatotoxicity requiring discontinuation of the drug.
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Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Monitoreo de Drogas , Femenino , Humanos , Pruebas de Función Hepática , Persona de Mediana Edad , Paclitaxel/uso terapéutico , TrastuzumabRESUMEN
(E)-4-[3-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure-anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3'-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.
Asunto(s)
Adamantano/análogos & derivados , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Cinamatos/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Adamantano/química , Adamantano/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Cinamatos/química , Dimerización , Inhibidores Enzimáticos/química , Humanos , Modelos MolecularesRESUMEN
BACKGROUND: Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi-institutional prospective trial. METHODS: Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate-specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration. RESULTS: A total of 210 eligible and evaluable patients had a median follow-up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of >or=50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression-free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12-month or greater progression-free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA-only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response. CONCLUSIONS: These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (>or=1 year) in approximately 19% of patients.
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Adenocarcinoma/sangre , Antagonistas de Andrógenos/uso terapéutico , Neoplasias Óseas/sangre , Orquiectomía , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Síndrome de Abstinencia a Sustancias/sangre , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Anciano , Anciano de 80 o más Años , Anilidas/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Supervivencia sin Enfermedad , Flutamida/uso terapéutico , Hormona Liberadora de Gonadotropina/administración & dosificación , Humanos , Imidazolidinas/uso terapéutico , Masculino , Persona de Mediana Edad , Nitrilos/uso terapéutico , Estudios Prospectivos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Síndrome de Abstinencia a Sustancias/etiología , Tasa de Supervivencia , Compuestos de Tosilo/uso terapéuticoRESUMEN
Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]ethenyl}-1H-tetrazole, 5-{4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorobenzylidene}thiazolidine-2,4-dione, and (3E)-4-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 microM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.
Asunto(s)
Adamantano/análogos & derivados , Antineoplásicos/síntesis química , Apoptosis , Cinamatos/síntesis química , Proteínas Tirosina Fosfatasas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Retinoides/síntesis química , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Movimiento Celular , Proliferación Celular/efectos de los fármacos , Cinamatos/farmacología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Humanos , Técnicas In Vitro , Microcirculación/citología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Ensayo de Unión Radioligante , Receptores Citoplasmáticos y Nucleares/biosíntesis , Retinoides/farmacología , EstereoisomerismoRESUMEN
6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) and 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) are inducers of apoptosis of malignant cells both in vitro and in vivo. Numerous mechanisms have been proposed for how these compounds exert this effect. This report shows that AHPN/3-Cl-AHPC binds specifically to the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), and this binding promotes interaction of the receptor with a corepressor complex that minimally contains Sin3A, N-CoR, histone deacetylase 4, and HSP90. Formation of the SHP-Sin3A complex is essential for the ability of AHPN and 3-Cl-AHPC to induce apoptosis, as both knockout SHP and knockdown of Sin3A compromise the proapoptotic activity of these compounds but not other apoptosis inducers. These results suggest that AHPN/3-Cl-AHPC and their analogues are SHP ligands and their induction of apoptosis is mediated by their binding to the SHP receptor.