RESUMEN
An attractive flower from the island of Madagascar has in part saved the lives of thousands of children with acute lymphoblastic leukemia (ALL). Random mutations and alterations to the genome led to the evolution of genes encoding enzymes, which would provide the periwinkle flower an arsenal of secondary metabolites to survive within the Madagascar ecosystem. Of the over 200 alkaloid compounds synthesized by the periwinkle, vincristine and vinblastine are the two most well-known being used for chemotherapy treatments, including for children with ALL. The complexities of the multi-step biosynthesis of vincristine and vinblastine, which has taken years to decode, highlight the importance of protecting the vast biodiversity on earth as other natural products that can save lives await to be discovered. This review addresses the discovery of vincristine and vinblastine, as well as the history of their existence, in nature.
RESUMEN
The abundance of genetic abnormalities and phenotypic heterogeneities in acute myeloid leukemia (AML) poses significant challenges to the development of improved treatments. Here, we demonstrated that a key growth arrest-specific gene 6/AXL axis is highly activated in cells from patients with AML, particularly in stem/progenitor cells. We developed a potent selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition, alone or in combination with venetoclax, potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells and shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have a direct translational impact on the treatment of AML and other cancers with high AXL activity.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Sistemas de Liberación de Medicamentos , Leucemia Mieloide Aguda , Células Madre Neoplásicas/enzimología , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Sulfonamidas/farmacología , Animales , Línea Celular Tumoral , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa del Receptor AxlRESUMEN
Acute myeloid leukaemia (AML) is a highly heterogeneous haematologic malignancy with poor prognosis. We previously showed synergistic antileukaemic interaction between exportin 1 (XPO1) inhibitor KPT-330 (Selinexor) and Bcl-2 inhibitor venetoclax (ABT-199) in preclinical models of AML, which was partially meditated by Mcl-1, although the full mechanism of action remains unknown. In this study, using real-time RT-PCR and Western blot analysis, we show that inhibition of XPO1 via KPT-330 or KPT-8602 (Eltanexor) decreases the mRNA and protein levels of c-Myc, CHK1, WEE1, RAD51 and RRM2. KPT-330 and KPT-8602 induce DNA damage, as determined by alkaline comet assay. In addition, we demonstrate that venetoclax enhances KPT-330- and KPT-8602-induced DNA damage, likely through inhibition of DNA damage repair. This study provides new insight into the molecular mechanism underlying the synergistic antileukaemic activity between venetoclax and XPO1 inhibitors against AML. Our data support the clinical evaluation of this promising combination therapy for the treatment of AML.
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Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/farmacología , Apoptosis , Compuestos Bicíclicos Heterocíclicos con Puentes , Línea Celular Tumoral , Daño del ADN , Humanos , Carioferinas , Leucemia Mieloide Aguda/genética , Receptores Citoplasmáticos y Nucleares , Sulfonamidas , Proteína Exportina 1RESUMEN
Acute myeloid leukemia (AML) is an aggressive disease with a low 5-year overall survival rate of 29.5%. Thus, more effective therapies are in need to prolong survival of AML patients. Mcl-1 is overexpressed in AML and is associated with poor prognosis, representing a promising therapeutic target. The oncoprotein c-Myc is also overexpressed in AML and is a significant prognostic factor. In addition, Mcl-1 is required for c-Myc induced AML, indicating that c-Myc-driven AML harbors a Mcl-1 dependency and co-targeting of Mcl-1 and c-Myc represents a promising strategy to eradicate AML. In this study, we investigated the role of c-Myc in the antileukemic activity of Mcl-1 selective inhibitor AZD5991 and the antileukemic activity of co-targeting of Mcl-1 and c-Myc in preclinical models of AML. We found that c-Myc protein levels negatively correlated with AZD5991 EC50s in AML cell lines and primary patient samples. AZD5991 combined with inhibition of c-Myc synergistically induced apoptosis in AML cell lines and primary patient samples, and cooperatively targeted leukemia progenitor cells. AML cells with acquired resistance to AZD5991 were resensitized to AZD5991 when c-Myc was inhibited. The combination also showed promising and synergistic antileukemic activity in vitro against AML cell lines with acquired resistance to the main chemotherapeutic drug AraC and primary AML cells derived from a patient at relapse post chemotherapy. The oncoprotein c-Myc represents a potential biomarker of AZD5991 sensitivity and inhibition of c-Myc synergistically enhances the antileukemic activity of AZD5991 against AML.
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Leucemia Mieloide Aguda , Compuestos Macrocíclicos , Humanos , Apoptosis , Línea Celular Tumoral , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/uso terapéutico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismoRESUMEN
Venetoclax is a promising agent in the treatment of acute myeloid leukemia, though its antileukemic activity is limited to combination therapies. Mcl-1 downregulation, Bim upregulation, and DNA damage have been identified as potential ways to enhance venetoclax activity. In this study, we combine venetoclax with the dual PI3K and histone deacetylase inhibitor CUDC-907, which can downregulate Mcl-1, upregulate Bim, and induce DNA damage, as well as downregulate c-Myc. We establish that CUDC-907 and venetoclax synergistically induce apoptosis in acute myeloid leukemia cell lines and primary acute myeloid leukemia patient samples ex vivo. CUDC-907 downregulates CHK1, Wee1, RRM1, and c-Myc, which were found to play a role in venetoclax-induced apoptosis. Interestingly, we found that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an acute myeloid leukemia cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of acute myeloid leukemia.
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Leucemia Mieloide Aguda , Fosfatidilinositol 3-Quinasas , Animales , Apoptosis , Compuestos Bicíclicos Heterocíclicos con Puentes , Línea Celular Tumoral , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Ratones , Morfolinas , Pirimidinas , Sulfonamidas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Targeting the androgen receptor (AR) signalling pathway remains the main therapeutic option for advanced prostate cancer. However, resistance to AR-targeting inhibitors represents a great challenge, highlighting the need for new therapies. Activation of the PI3K/AKT pathway and increased expression of histone deacetylases (HDACs) are common aberrations in prostate cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy for this patient population. Previous reports demonstrated that combination of PI3K inhibitors (PI3KIs) with histone deacetylase inhibitors (HDACIs) resulted in synergistic antitumour activities against preclinical models of prostate cancer. In this study, we demonstrate that the novel dual PI3K and HDAC inhibitor CUDC-907 has promising antitumour activity against prostate cancer cell lines in vitro and castration-resistant LuCaP 35CR patient-derived xenograft (PDX) mouse model in vivo. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bcl-xL, Bim and c-Myc. Further, down-regulation of Wee1, CHK1, RRM1 and RRM2 contributed to CUDC-907-induced DNA damage and apoptosis. In the LuCaP 35CR PDX model, treatment with CUDC-907 resulted in significant inhibition of tumour growth. These findings support the clinical development of CUDC-907 for the treatment of prostate cancer.
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Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Morfolinas/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Pirimidinas/uso terapéutico , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Daño del ADN , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Morfolinas/farmacología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Pirimidinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML). METHODS: To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m2 ) before and in combination with fludarabine and cytarabine. RESULTS: All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status. CONCLUSIONS: Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.
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Panobinostat/farmacología , Panobinostat/farmacocinética , Panobinostat/uso terapéutico , Adolescente , Adulto , Niño , Femenino , Humanos , Leucemia Mieloide Aguda , Masculino , Recurrencia Local de Neoplasia , Adulto JovenRESUMEN
Fetoplacental neuroblastoma metastasis has been postulated as a mechanism accounting for concordant cases where one twin develops a primary tumour and the second twin manifests the disease without an identifiable primary site. These tumours may originate and spread concomitantly due to the same genetic background shared by monozygotic twins. This study investigated the molecular profile of stage MS neuroblastoma presenting concomitantly in monozygotic twins. Comparative genomic hybridisation (aCGH) was done for each of the twin liver tumour and peripheral blood samples at diagnosis. Comparison of copy-number variation (CNV) regions revealed a set of CNVs that were common to both tumour specimens and not apparent in the blood. The CNV signature in both twins' tumours was highly similar, suggesting a common clonal origin. Additional findings included large deletion of chromosome 10 and amplification of chromosome 17. Notably, both liver samples had amplification of a short region involving DEIN (chromosome 4q34.1). Similar CNVs strongly support a common clonal origin and metastatic spread from one twin to the other. DEIN is a long-coding RNA (IncRNA) that has been found highly expressed in stage MS neuroblastoma and is likely involved in biological processes such as cell migration and metastasis.
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Neoplasias de las Glándulas Suprarrenales/genética , Variaciones en el Número de Copia de ADN/genética , Neoplasias Hepáticas/genética , Neuroblastoma/genética , Neoplasias de las Glándulas Suprarrenales/patología , Deleción Cromosómica , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 17/genética , Hibridación Genómica Comparativa , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Lactante , Neoplasias Hepáticas/patología , Metástasis de la Neoplasia , Neuroblastoma/patología , ARN Largo no Codificante/genética , Gemelos Monocigóticos/genéticaRESUMEN
Patients with myeloid leukemia of Down syndrome (ML-DS) have favorable event-free survival (EFS), but experience significant treatment-related morbidity and mortality. ML-DS blast cells ex vivo have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimizing drug dosing may improve outcomes while reducing toxicity. The Children's Oncology Group (COG) AAML0431 trial consisted of 4 cycles of induction and 2 cycles of intensification therapy based on the treatment schema of the previous COG A2971 trial with several modifications. High-dose araC (HD-araC) was used in the second induction cycle instead of the intensification cycle, and 1 of 4 daunorubicin-containing induction cycles was eliminated. For 204 eligible patients, 5-year EFS was 89.9% and overall survival (OS) was 93.0%. The 5-year OS for 17 patients with refractory/relapsed leukemia was 34.3%. We determined the clinical significance of minimal residual disease (MRD) levels as measured by flow cytometry on day 28 of induction I. MRD measurements, available for 146 of the 204 patients, were highly predictive of treatment outcome; 5-year disease-free survival for MRD-negative patients (n = 125) was 92.7% vs 76.2% for MRD-positive patients (n = 21) (log-rank P = .011). Our results indicated that earlier use of HD-araC led to better EFS and OS in AAML0431 than in past COG studies. A 25% reduction in the cumulative daunorubicin dose did not impact outcome. MRD, identified as a new prognostic factor for ML-DS patients, can be used for risk stratification in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00369317.
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Antibióticos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Síndrome de Down/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Análisis Citogenético , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Supervivencia sin Enfermedad , Síndrome de Down/genética , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/genética , Masculino , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Resultado del TratamientoRESUMEN
Induction therapy for patients with acute myeloid leukemia (AML) has remained largely unchanged for over 40 years, while overall survival rates remain unacceptably low, highlighting the need for new therapies. The PI3K/Akt pathway is constitutively active in the majority of patients with AML. Given that histone deacetylase inhibitors have been shown to synergize with PI3K inhibitors in preclinical AML models, we investigated the novel dual-acting PI3K and histone deacetylase inhibitor CUDC-907 in AML cells both in vitro and in vivo We demonstrated that CUDC-907 induces apoptosis in AML cell lines and primary AML samples and shows in vivo efficacy in an AML cell line-derived xenograft mouse model. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bim, and c-Myc. CUDC-907 induced DNA damage in AML cells while sparing normal hematopoietic cells. Downregulation of CHK1, Wee1, and RRM1, and induction of DNA damage also contributed to CUDC-907-induced apoptosis of AML cells. In addition, CUDC-907 treatment decreased leukemia progenitor cells in primary AML samples ex vivo, while also sparing normal hematopoietic progenitor cells. These findings support the clinical development of CUDC-907 for the treatment of AML.
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Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Morfolinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Pirimidinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Genes myc , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Although significant advances in experimental high throughput screening (HTS) have been made for drug lead identification, in silico virtual screening (VS) is indispensable owing to its unique advantage over experimental HTS, target-focused, cheap, and efficient, albeit its disadvantage of producing false positive hits. For both experimental HTS and VS, the quality of screening libraries is crucial and determines the outcome of those studies. In this paper, we first reviewed the recent progress on screening library construction. We realized the urgent need for compiling high-quality screening libraries in drug discovery. Then we compiled a set of screening libraries from about 20 million druglike ZINC molecules by running fingerprint-based similarity searches against known drug molecules. Lastly, the screening libraries were objectively evaluated using 5847 external actives covering more than 2000 drug targets. The result of the assessment is very encouraging. For example, with the Tanimoto coefficient being set to 0.75, 36% of external actives were retrieved and the enrichment factor was 13. Additionally, drug target family specific screening libraries were also constructed and evaluated. The druglike screening libraries are available for download from https://mulan.pharmacy.pitt.edu .
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Simulación por Computador , Proteínas/química , Bibliotecas de Moléculas Pequeñas/química , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Bases de Datos Farmacéuticas , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto RendimientoRESUMEN
The antiapoptotic Bcl-2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl-2-selective inhibitor ABT-199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl-1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl-1 levels in cancer cells. Thus, we hypothesized that the XPO1-selective inhibitor KPT-330 (Selinexor) can synergize with ABT-199 to induce apoptosis in AML cells through down-regulation of Mcl-1. The combination of KPT-330 and ABT-199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT-330 treatment decreased Mcl-1 protein after apoptosis initiation. However, binding of Bim to Mcl-1 induced by ABT-199 was abrogated by KPT-330 at the same time as apoptosis initiation. KPT-330 treatment increased binding of Bcl-2 to Bim but was overcome by ABT-199 treatment, demonstrating that KPT-330 and ABT-199 reciprocally overcome apoptosis resistance. Mcl-1 knockdown and overexpression confirmed its critical role in the antileukaemic activity of the combination. In summary, KPT-330 treatment, alone and in combination with ABT-199, modulates Mcl-1, which plays an important role in the antileukaemic activity of the combination.
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Carioferinas/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptores Citoplasmáticos y Nucleares/genética , Adulto , Anciano , Apoptosis/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hidrazinas/administración & dosificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/administración & dosificación , Triazoles/administración & dosificación , Proteína Exportina 1RESUMEN
Children with Down syndrome (DS) are at increased risk for acute myeloid leukemias (ML-DS) characterized by mixed megakaryocytic and erythroid phenotype and by acquired mutations in the GATA1 gene resulting in a short GATA1s isoform. The chromosome 21 microRNA (miR)-125b cluster has been previously shown to cooperate with GATA1s in transformation of fetal hematopoietic progenitors. In this study, we report that the expression of miR-486-5p is increased in ML-DS compared with non-DS acute megakaryocytic leukemias (AMKLs). miR-486-5p is regulated by GATA1 and GATA1s that bind to the promoter of its host gene ANK1. miR-486-5p is highly expressed in mouse erythroid precursors and knockdown (KD) in ML-DS cells reduced their erythroid phenotype. Ectopic expression and KD of miR-486-5p in primary fetal liver hematopoietic progenitors demonstrated that miR-486-5p cooperates with Gata1s to enhance their self renewal. Consistent with its activation of AKT, overexpression and KD experiments showed its importance for growth and survival of human leukemic cells. Thus, miR-486-5p cooperates with GATA1s in supporting the growth and survival, and the aberrant erythroid phenotype of the megakaryocytic leukemias of DS.
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Síndrome de Down/genética , Eritropoyesis/genética , Leucemia Mieloide Aguda/genética , MicroARNs/fisiología , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Preescolar , Síndrome de Down/complicaciones , Síndrome de Down/fisiopatología , Células Eritroides/metabolismo , Células HEK293 , Humanos , Células K562 , Leucemia Mieloide Aguda/patología , Megacariocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/genética , Células Tumorales CultivadasRESUMEN
Diffuse intrinsic pontine glioma (DIPG) remains a devastating disease. Panobinostat has been shown to have therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models; however, clinical data in patients with DIPG are lacking. We present 2 cases of DIPG, who were treated with panobinostat at 22 to 25 mg/m/dose, 3 times weekly for 2 weeks in 3-week cycles and concomitant reirradiation after disease progression. Two episodes of asymptomatic thrombocytopenia were observed in 1 patient. Hyperacetylation of histone H4 of peripheral blood mononuclear cells was evident following treatment. In our experience, panobinostat administered with reirradiation was well tolerated at a relatively higher dose than that used in adult studies.
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Glioma/tratamiento farmacológico , Glioma/radioterapia , Ácidos Hidroxámicos/administración & dosificación , Indoles/administración & dosificación , Acetilación , Preescolar , Terapia Combinada , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Histonas/metabolismo , Humanos , Panobinostat , Reirradiación , Trombocitopenia/etiología , Resultado del TratamientoAsunto(s)
Accesibilidad a los Servicios de Salud , Leucemia Mieloide Aguda , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Adulto , Niño , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Tirosina Quinasa 3 Similar a fms/genéticaAsunto(s)
Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Betacoronavirus , COVID-19 , Niño , Humanos , Pandemias , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevención & control , Factores de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: Despite advances in treatment regimens, patients with high-risk neuroblastoma have long-term survival rates of < 40%. Wee1 inhibition in combination with CHK1 inhibition has shown promising results in neuroblastoma cells. In addition, it has been demonstrated that panobinostat can downregulate CHK1. Therefore, combination of panobinostat and MK-1775 may result in synergistic cytotoxicity against neuroblastoma cell lines. PROCEDURE: In vitro cytotoxicities of panobinostat and MK-1775 at clinically achievable concentrations, either alone or in combination, were evaluated in SK-N-AS, SK-N-DZ, and SK-N-BE(2) high-risk neuroblastoma cell lines using MTT assays. The mechanism of antitumor interaction was investigated using propidium iodide (PI) staining and flow cytometry analysis to determine apoptosis, as well as Western blotting to assess expression of phosphorylated CDK1/2, CHK1, and H2AX. RESULTS: Treatment of neuroblastoma cell lines with 500 nM MK-1775 caused growth arrest and apoptosis in SK-N-DZ and SK-N-AS, while it had minimal effect on the SK-N-BE(2) cell line. The combination of panobinostat and MK-1775 resulted in synergistic antitumor interactions in all three of the cell lines tested. MK-1775 treatment in SK-N-BE(2) cells induced increased levels of p-CHK1(S345) , which could be decreased by the addition of panobinostat. This was accompanied by increased DNA damage and apoptosis. CONCLUSIONS: The combination of panobinostat and MK-1775 has synergistic antitumor activity against neuroblastoma cell lines and holds promise as a potential treatment strategy for the management of high-risk neuroblastoma patients.
Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Histona Desacetilasas/química , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Pirimidinas/farmacología , Western Blotting , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Panobinostat , Pirimidinonas , Factores de Riesgo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Most Down syndrome children with acute myeloid leukemia (DS-AML) have an overall excellent prognosis, however, patients who suffer an induction failure or relapse, have an extremely poor prognosis. Hence, new therapies need to be developed for this subgroup of DS-AML patients. One new therapeutic approach is preventing cell cycle checkpoint activation by inhibiting the upstream kinase wee1 with the first-in-class inhibitor MK-1775 in combination with the standard genotoxic agent cytarabine (AraC). PROCEDURE: Using the clinically relevant DS-AML cell lines CMK and CMY, as well as ex vivo primary DS-AML patient samples, the ability of MK-1775 to enhance the cytotoxicity of AraC was investigated with MTT assays. The mechanism by which MK-1775 enhanced AraC cytotoxicity was investigated in the cell lines using Western blots to probe CDK1 and H2AX phosphorylation and flow cytometry to determine apoptosis, cell cycle arrest, DNA damage, and aberrant mitotic entry. RESULTS: MK-1775 alone had modest single-agent activity, however, MK-1775 was able to synergize with AraC in causing proliferation arrest in both cell lines and primary patient samples, and enhance AraC-induced apoptosis. MK-1775 was able to decrease inhibitory CDK1(Y15) phosphorylation at the relatively low concentration of 100 nM after only 4 hours. Furthermore, it was able to enhance DNA damage induced by AraC and partially abrogate cell cycle arrest. Importantly, the DNA damage enhancement appeared in early S-phase. CONCLUSIONS: MK-1775 is able to enhance the cytotoxicity of AraC in DS-AML cells and presents a promising new treatment approach for DS-AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Síndrome de Down/complicaciones , Leucemia Mieloide Aguda/enzimología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Apoptosis/efectos de los fármacos , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Niño , Citarabina/administración & dosificación , Sinergismo Farmacológico , Citometría de Flujo , Humanos , Leucemia Mieloide Aguda/complicaciones , Pirimidinonas , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.
RESUMEN
The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.