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Hematopoyesis , Leucemia , Humanos , Hematopoyesis/efectos de los fármacos , Animales , Leucemia/inmunología , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/genética , RatonesRESUMEN
The cell signaling pathways involved in the antiproliferative activities of T. rosea inner bark remain unexplored. This study evaluated the apoptotic effects of two iridoids from the inner bark of T. rosea and apicidin on THP-1 cells. The cytotoxic effects of the extract and the pure compounds on THP-1 and Jurkat cells were also evaluated using the MTT assay. The apoptotic effect was determined by measuring the mitochondrial membrane potential. The expression of mRNA and MAPK kinase, Bax, and Bcl-2 proteins was detected by Western blotting and RT-qPCR, respectively. The extract and the compounds evaluated increased the percentage of apoptotic cells. Depolarization of the mitochondrial membrane was observed, and the number of cells in the G0/G1 phase increased. Catalposide and specioside significantly increased p38 protein expression, mostly in cells pretreated with apicidin. The p38 MAPK signaling pathway is at least one of the pathways by which the n-butanol extract obtained from Tabebuia rosea, catalposide, and specioside exerts its apoptotic effect on THP-1 cells, and this effect generates a response in the G0/G1 phase and subsequent cell death. In addition, there was depolarization of the mitochondrial membrane, an effect that was related to the participation of the proapoptotic protein Bax.
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Apoptosis , Potencial de la Membrana Mitocondrial , Corteza de la Planta , Extractos Vegetales , Tabebuia , Humanos , Apoptosis/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Corteza de la Planta/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Tabebuia/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/aislamiento & purificación , Células Jurkat , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Leucemia/patología , 1-Butanol/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Células THP-1 , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacosRESUMEN
This article reports a study designed to evaluate the effectiveness of regular oral care protocol developed specifically for adults in intensive care to prevent mucositis. Data were collected using oral mucositis assessment scale, oral cavity assessment tool, and the National Cancer Institute Common Toxicity Criteria. The results indicated that oral mucositis can be reduced through the practice of administering oral care in accordance with oral health care guidelines. Oral care implemented in line with an evidence-based oral care guide and frequent observation of patients is the most important step in preventing oral mucositis.
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Higiene Bucal , Estomatitis , Humanos , Estomatitis/prevención & control , Estomatitis/etiología , Estudios Prospectivos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Leucemia/complicaciones , Leucemia/tratamiento farmacológico , Unidades de Cuidados Intensivos , Índice de Severidad de la EnfermedadRESUMEN
Antibody-drug conjugate(ADC)contain monoclonal antibodies that target-specific tumor antigens, cytotoxic payloads, and linkers. ADCs use antibodies to selectively act on tumors, making them more effective and less toxic. In Japan, 4 drugs are approved as ADCs for leukemia and lymphoma: gemtuzumab ozogamicin(GO)consists of an anti-CD33 monoclonal antibody bound to calicheamicin via a linker, approved for relapsed/refractory acute myeloid leukemia. Brentuximab vedotin (BV)has anti-CD30 antibodies bound to MMAE via a linker and is approved for CD30-positive Hodgkin's lymphoma, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. BV, in combination with multi-agent chemotherapy, resulted in significantly prolonged progression-free survival(PFS)in classical Hodgkin's lymphoma and peripheral T-cell lymphoma compared to the control group. Inotuzumab ozogamicin(IO)has an anti-CD22 antibody bound to calicheamicin via a linker, approved for relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia. In relapsed/refractory B-cell acute lymphoblastic leukemia, IO showed a higher complete remission rate than the control group. Polatuzumab vedotin(PV)has an anti-CD79b monoclonal antibody bounds to MMAE via a linker, approved for diffuse large B-cell lymphoma(DLBCL). In DLBCL patients with an international prognostic index score(IPI score)of 2 or higher, the combination of PV plus rituximab, cyclophosphamide, doxorubicin, and prednisone(PV+R-CHP)extended PFS at 2 years compared with R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), which has long been the standard of care. As shown, ADCs exhibit high therapeutic efficacy in leukemia and lymphoma treatment, but many aspects of their resistance mechanisms remain unclear and require further research.
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Inmunoconjugados , Leucemia , Linfoma , Humanos , Inmunoconjugados/uso terapéutico , Leucemia/tratamiento farmacológico , Leucemia/inmunología , Linfoma/tratamiento farmacológico , Linfoma/inmunología , Antineoplásicos/uso terapéuticoRESUMEN
From previous studies, it is evident that metal-organic gold(I) complexes have antiproliferative activities. The aim of this study is not only to find new anticancer agents but also to overcome existing cytostatic resistance in cancer cells. The synthesis and medicinal evaluation of two cationic 1,3-disubstituted gold(I) bis-tetrazolylidene complexes 1 and 2 are reported. To determine apoptosis-inducing properties of the complexes, DNA fragmentation was measured using propidium iodide staining followed by flow cytometry. Gold(I) complex 1 targets explicitly malignant cells, effectively inhibiting their growth and selectively inducing apoptosis without signs of necrosis. Even in cells resistant to common treatments such as doxorubicin, it overcomes multidrug resistance and sensitizes existing drug-resistant cells to common cytostatic drugs. It is assumed that gold(I) complex 1 involves the mitochondrial pathway in apoptosis and targets members of the BCL-2 family, enhancing its potential as a therapeutic agent in cancer treatment.
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Antineoplásicos , Apoptosis , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Oro , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Oro/química , Oro/farmacología , Línea Celular Tumoral , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia/metabolismo , Metano/análogos & derivados , Metano/farmacología , Metano/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacosRESUMEN
Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C-R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C-R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C-R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities.
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Antineoplásicos , Apoptosis , Proliferación Celular , Leucemia , Linfoma , Proteolisis , Humanos , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proteolisis/efectos de los fármacos , Linfoma/tratamiento farmacológico , Linfoma/patología , Linfoma/metabolismo , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , Péptidos de Penetración Celular/síntesis química , Estructura Molecular , Células K562 , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de MedicamentosRESUMEN
The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in mixed-lineage leukemia-rearranged (MLL-r) leukemia. ENL relies on its reader domain to recognize histone lysine acylation promoting oncogenic gene expression and leukemia progression. Here, we report the development of MS41, a highly potent and selective von Hippel-Lindau-recruiting ENL degrader that effectively inhibits the growth of ENL-dependent leukemia cells. MS41-induced ENL degradation reduces the chromatin occupancy of ENL-associated transcription elongation machinery, resulting in the suppression of key oncogenic gene expression programs and the activation of differentiation genes. MS41 is well-tolerated in vivo and substantially suppresses leukemia progression in a xenograft mouse model of MLL-r leukemia. Notably, MS41 also induces the degradation of mutant ENL proteins identified in Wilms' tumors. Our findings emphasize the therapeutic potential of pharmacological ENL degradation for treating ENL-dependent cancers, making MS41 not only a valuable chemical probe but also potential anticancer therapeutic for further development.
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Progresión de la Enfermedad , Leucemia , Humanos , Animales , Ratones , Línea Celular Tumoral , Leucemia/genética , Leucemia/patología , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Factores de Elongación Transcripcional/metabolismo , Factores de Elongación Transcripcional/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Proteolisis/efectos de los fármacos , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Proliferación Celular/efectos de los fármacosRESUMEN
HOXA9, an important transcription factor (TF) in hematopoiesis, is aberrantly expressed in numerous cases of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and is a strong indicator of poor prognosis in patients. HOXA9 is a proto-oncogene which is both sufficient and necessary for leukemia transformation. HOXA9 expression in leukemia correlates with patient survival outcomes and response to therapy. Chromosomal transformations (such as NUP98-HOXA9), mutations, epigenetic dysregulation (e.g., MLL- MENIN -LEDGF complex or DOT1L/KMT4), transcription factors (such as USF1/USF2), and noncoding RNA (such as HOTTIP and HOTAIR) regulate HOXA9 mRNA and protein during leukemia. HOXA9 regulates survival, self-renewal, and progenitor cell cycle through several of its downstream target TFs including LMO2, antiapoptotic BCL2, SOX4, and receptor tyrosine kinase FLT3 and STAT5. This dynamic and multilayered HOXA9 regulome provides new therapeutic opportunities, including inhibitors targeting DOT1L/KMT4, MENIN, NPM1, and ENL proteins. Recent findings also suggest that HOXA9 maintains leukemia by actively repressing myeloid differentiation genes. This chapter summarizes the recent advances understanding biochemical mechanisms underlying HOXA9-mediated leukemogenesis, the clinical significance of its abnormal expression, and pharmacological approaches to treat HOXA9-driven leukemia.
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Regulación Leucémica de la Expresión Génica , Proteínas de Homeodominio , Nucleofosmina , Proto-Oncogenes Mas , Humanos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Animales , Leucemia/genética , Leucemia/metabolismo , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
INTRODUCTION: Skeletal muscle function is an important prognostically relevant indicator in patients with acute leukemia (AL), but skeletal dysfunction during chemotherapy is not well understood. This study aimed to investigate the factors that influence changes in skeletal muscle function from before the start of chemotherapy to before allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: This was a retrospective cohort study that included 90 patients with AL who underwent chemotherapy before transplantation to perform allo-HSCT (men, 67.3%; median age, 53 years). The outcome measure was defined as changes in skeletal muscle function from before chemotherapy to before allo-HSCT, and was assessed by measuring the psoas muscle index (PMI) as skeletal muscle quantity and computed tomography values (CTV) as skeletal muscle quality using a computed tomography scanner. We examined the differences in PMI and CTV before chemotherapy and allo-HSCT, and the factors associated with changes in PMI. RESULT: The mean PMI for before chemotherapy and allo-HSCT were 4.6 ± 1.4 cm2/m2 and 4.0 ± 1.3 cm2/m2 and significant differences were observed (p < 0.001). However, the mean CTV before chemotherapy and allo-HSCT were 47.3 ± 4.5 HU and 47.4 ± 5.0 HU, respectively, and no significant differences were found (p = 0.798). In stepwise multiple regression analysis, age and sex were identified as factors related to changes in PMI (age, p = 0.019; sex, p = 0.001). CONCLUSION: We found that skeletal muscle quantity decreased during chemotherapy in patients with AL and was influenced by male sex and older age. TRIAL REGISTRATION NUMBER: TRIAL REGISTRATION NUMBER: 34-096(11,243). Date of registration: September 11, 2023.
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Trasplante de Células Madre Hematopoyéticas , Músculo Esquelético , Humanos , Masculino , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Adulto , Trasplante de Células Madre Hematopoyéticas/métodos , Músculo Esquelético/fisiopatología , Anciano , Tomografía Computarizada por Rayos X/métodos , Estudios de Cohortes , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/terapia , Músculos Psoas , Adulto Joven , Leucemia/terapia , Leucemia/tratamiento farmacológico , Trasplante Homólogo/métodos , Enfermedad Aguda , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificaciónRESUMEN
Anticancer theranostic nanocarriers have the potential to enhance the efficacy of pharmaceutical evaluation of drugs. Semiconductor nanocrystals, also known as quantum dots (QDs), are particularly promising components of drug carrier systems due to their small sizes and robust photoluminescence properties. Herein, bright CdZnSeS quantum dots were synthesized in a single step via the hot injection method. The particles have a quasi-core/shell structure as evident from the high quantum yield (85 %), which decreased to 41 % after water solubilization. These water solubilized QDs were encapsulated into gallic acid / alginate (GA-Alg) matrices to fabricate imaging QDs@mod-PAA/GA-Alg particles with enhanced stability in aqueous media. Cell viability assessments demonstrated that these nanocarriers exhibited viability ranging from 63 % to 83 % across all tested cell lines. Furthermore, the QDs@mod-PAA/GA-Alg particles were loaded with betulinic acid (BA) and ceranib-2 (C2) for in vitro drug release studies against HL-60 leukemia and PC-3 prostate cancer cells. The BA loaded QDs@mod-PAA/GA-Alg had a half-maximal inhibitory concentration (IC50) of 8.76 µg/mL against HL-60 leukemia cells, which is 3-fold lower than that of free BA (IC50 = 26.55 µg/mL). Similar enhancements were observed with nanocarriers loaded with C2 and simultaneously with both BA and C2. Additionally, BA:C2 loaded QDs@mod-PAA/GA-Alg nanocarriers displayed a similar enhancement (IC50 = 3.37 µg/mL compared against IC50 = 11.68 µg/mL for free BA:C2). The C2 loaded QDs@mod-PAA/GA-Alg nanocarriers had an IC50 = 2.24 µg/mL against HL-60 cells. C2 and BA loaded QDs@mod-PAA/GA-Alg NCr had IC50 values of 7.37 µg/mL and 24.55 µg/mL against PC-3 cells, respectively.
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Antineoplásicos , Supervivencia Celular , Neoplasias de la Próstata , Puntos Cuánticos , Nanomedicina Teranóstica , Puntos Cuánticos/química , Humanos , Masculino , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Tamaño de la Partícula , Leucemia/tratamiento farmacológico , Leucemia/patología , Ensayos de Selección de Medicamentos Antitumorales , Compuestos de Selenio/química , Compuestos de Selenio/farmacología , Compuestos de Cadmio/química , Propiedades de Superficie , Liberación de Fármacos , Alginatos/química , Portadores de Fármacos/química , Compuestos de Zinc/química , Proliferación Celular/efectos de los fármacos , Células PC-3 , Células HL-60RESUMEN
INTRODUCTION: The global need for antifungal stewardship is driven by spreading antimicrobial and antifungal resistance. Triazoles are the only oral and relatively well-tolerated class of antifungal medications, and usage is associated with acquired resistance and species replacement with intrinsically resistant organisms. On a per-patient basis, hematology patients are the largest inpatient consumers of antifungal drugs, but are also the most vulnerable to invasive fungal disease. AREAS COVERED: In this review we discuss available and forthcoming antifungal drugs, antifungal prophylaxis and empiric antifungal therapy, and how a screening based and diagnostic-driven approach may be used to reduce antifungal consumption. Finally, we discuss components of an antifungal stewardship program, interventions that can be employed, and how impact can be measured. The search methodology consisted of searching PubMed for journal articles using the term antifungal stewardship plus program, intervention, performance measure or outcome before 1 January 2024. EXPERT OPINION: Initial focus should be on implementing effective antifungal stewardship programs by developing and implementing local guidelines and using interventions, such as post-prescription review and feedback, which are known to be effective. Technologies such as microbiome analysis and machine learning may allow the development of truly individualized risk-factor-based approaches to antifungal stewardship in the future.
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Antifúngicos , Humanos , Antifúngicos/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos/métodos , Farmacorresistencia Fúngica , Micosis/tratamiento farmacológico , Leucemia/tratamiento farmacológico , Infecciones Fúngicas Invasoras/tratamiento farmacológicoRESUMEN
Anti-cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin-I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin-I, which can self-assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin-I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin-I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K-AKT-mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin-I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin-I can provide new insights into the mechanism of ACPs, and Lycosin-I, which is characterized by high potency and specificity, can be a promising lead for the development of anti-leukemia drugs.
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Leucemia , Ratones Desnudos , Animales , Ratones , Humanos , Leucemia/tratamiento farmacológico , Células K562 , Apoptosis/efectos de los fármacos , Venenos de Araña/farmacología , Venenos de Araña/química , Modelos Animales de Enfermedad , Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Péptidos/farmacología , Péptidos Catiónicos AntimicrobianosRESUMEN
Selinexor, a first-in-class exportin1 (XPO1) inhibitor, is an attractive anti-tumor agent because of its unique mechanisms of action; however, its dose-dependent toxicity and lack of biomarkers preclude its wide use in clinical applications. To identify key molecules/pathways regulating selinexor sensitivity, we performed genome-wide CRISPR/Cas9 dropout screens using two B-ALL lines. We identified, for the first time, that paralogous DDX19A and DDX19B RNA helicases modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export. While single depletion of either DDX19A or DDX19B barely altered MCL1 protein levels, depletion of both significantly attenuated MCL1 mRNA nuclear export, reducing MCL1 protein levels. Importantly, combining selinexor treatment with depletion of either DDX19A or DDX19B markedly induced intrinsic apoptosis of leukemia cells, an effect rescued by MCL1 overexpression. Analysis of Depmap datasets indicated that a subset of T-ALL lines expresses minimal DDX19B mRNA levels. Moreover, we found that either selinexor treatment or DDX19A depletion effectively induced apoptosis of T-ALL lines expressing low DDX19B levels. We conclude that XPO1 and DDX19A/B coordinately regulate cellular MCL1 levels and propose that DDX19A/B could serve as biomarkers for selinexor treatment. Moreover, pharmacological targeting of DDX19 paralogs may represent a potential strategy to induce intrinsic apoptosis in leukemia cells.
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ARN Helicasas DEAD-box , Hidrazinas , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , ARN Mensajero , Triazoles , Triazoles/farmacología , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Hidrazinas/farmacología , ARN Mensajero/genética , Leucemia/metabolismo , Leucemia/tratamiento farmacológico , Leucemia/genética , Leucemia/patología , Apoptosis/efectos de los fármacos , Transporte Activo de Núcleo Celular/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Antineoplásicos/farmacologíaRESUMEN
In their recent paper published in Nature, Luo et al.1 investigate the cancer-cell-intrinsic roles of the PI3Kγ complex in leukemia. Their findings pinpoint PI3Kγ inhibition as a possible novel treatment avenue for a subset of acute leukemias.
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Fosfatidilinositol 3-Quinasa Clase Ib , Leucemia , Inhibidores de las Quinasa Fosfoinosítidos-3 , Humanos , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/químicaRESUMEN
l-asparaginases play a crucial role in the treatment of acute lymphoblastic leukemia (ALL), a type of cancer that mostly affects children and teenagers. However, it is common for these molecules to cause adverse reactions during treatment. These downsides ignite the search for novel asparaginases to mitigate these problems. Thus, this work aimed to produce and characterize a recombinant asparaginase from Phaseolus vulgaris (Asp-P). In this study, Asp-P was expressed in Escherichia coli with high yields and optimum activity at 40 °C, pH 9.0. The enzyme Km and Vmax values were 7.05 mM and 1027 U/mg, respectively. Asp-P is specific for l-asparagine, showing no activity against l-glutamine and other amino acids. The enzyme showed a higher cytotoxic effect against Raji than K562 cell lines, but only at high concentrations. In silico analysis indicated that Asp-P has lower immunogenicity than a commercial enzyme. Asp-P induced biofilm formation by Candida sp. due to sublethal dose, showing an underexplored potential of asparaginases. The absence of glutaminase activity, lower immunogenicity and optimal activity similar to physiological temperature conditions are characteristics that indicate Asp-P as a potential new commercial enzyme in the treatment of ALL and its underexplored application in the treatment of other diseases.
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Asparaginasa , Phaseolus , Proteínas Recombinantes , Asparaginasa/química , Asparaginasa/farmacología , Asparaginasa/genética , Asparaginasa/inmunología , Phaseolus/química , Humanos , Cinética , Proteínas Recombinantes/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Leucemia/tratamiento farmacológico , Células K562 , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Biopelículas/efectos de los fármacos , Concentración de Iones de Hidrógeno , TemperaturaRESUMEN
In therapies, curcumin is now commonly formulated in liposomal form, administered through injections or creams. This enhances its concentration at the cellular level compared to its natural form ingestion. Due to its hydrophobic nature, curcumin is situated in the lipid part of the membrane, thereby modifying its properties and influencing processes The aim of the research was to investigate whether the toxicity of specific concentrations of curcumin, assessed through biochemical tests for the SK-N-SH and H-60 cell lines, is related to structural changes in the membranes of these cells, caused by the localization of curcumin in their hydrophobic regions. Biochemical tests were performed using spectrophotometric methods. Langmuir technique were used to evaluate the interaction of the curcumin with the studied lipids. Direct introduction of curcumin into the membranes alters their physicochemical parameters. The extent of these changes depends on the initial properties of the membrane. In the conducted research, it has been demonstrated that curcumin may exhibit toxicity to human cells. The mechanism of this toxicity is related to its localization in cell membranes, leading to their dysfunction. The sensitivity of cells to curcumin presence depends on the saturation level of their membranes; the more rigid the membrane, the lower the concentration of curcumin causes its disruption.
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Membrana Celular , Curcumina , Neuroblastoma , Curcumina/farmacología , Curcumina/química , Humanos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patología , Línea Celular Tumoral , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Leucemia/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
Beauvericin (BEA), Enniatin B (ENN B), and Ochratoxin A (OTA) are mycotoxins produced by fungi species. Their main effect on several organs and systems is associated with chronic exposure going from immunotoxicity, estrogenic disorders, and renal failure to cancer (in animals and humans). OTA belongs to Group 1 according to the International Agency for Research in Cancer (IARC) and it has legislated limited values; not happening for BEA nor ENN B. Exposure to mixtures of mycotoxins occurs through food intake in daily consumption. The aim of this study was to evaluate the implication of BEA, ENN B, and OTA individually and combined in producing cytotoxicity in cells for immunological studies and cancer cell lines (human leukemia cells (HL-60), fresh human peripheral blood mononuclear cells (PBMCs), and human breast cancer (MDA-MB-231) cells). Cells were treated for 4 h and 24 h at different concentrations of BEA, ENN B, and OTA, respectively. Viability assays were carried out by flow cytometry using DAPI (4',6-diamindino-2-phenylindole, dihydrochloride) as a viability dye and the potential effects of synergism, addition, and antagonism were assessed through the Chou and Talalay method. Individual OTA treatment exerted the greatest cytotoxicity for PBMC cells (IC50 0.5 µM) while ENN B for HL-60 (IC50 0.25 µM) and MDA-MB-231 (IC50 0.15 µM). In binary combination [ENN B + OTA] resulted in exerting the greatest cytotoxicity for HL-60 and MDA-MB-231 cells; while [BEA + OTA] in PBMC cells. The triple combination resulted in being highly cytotoxic for PBMC cells compared to HL-60 and MDA-MB-231 cells. In summary, PBMC cells were the most sensible cells for all three mycotoxins and the presence of OTA in any of the combinations had the greatest toxicity causing synergism as the most common cytotoxic effect.
Asunto(s)
Neoplasias de la Mama , Supervivencia Celular , Depsipéptidos , Leucocitos Mononucleares , Ocratoxinas , Humanos , Depsipéptidos/toxicidad , Ocratoxinas/toxicidad , Leucocitos Mononucleares/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Femenino , Leucemia/tratamiento farmacológicoRESUMEN
sulfur-containing amino acids have been reported to patriciate in gene regulation, DNA methylation, protein synthesis and other physiological or pathological processes. In recent years, metabolism-related molecules of sulfur-containing amino acids affecting the occurrence, development and treatment of tumors have been implicated in various disorders, especially in leukemia. Here, we summarize current knowledge on the sulfur-containing amino acid metabolism pathway in leukemia and examine ongoing efforts to target this pathway, including treatment strategies targeting (a) sulfur-containing amino acids, (b) metabolites of sulfur-containing amino acids, and (c) enzymes and cofactors related to sulfur-containing amino acid metabolism in leukemia. Future leukemia therapy will likely involve innovative strategies targeting the sulfur-containing amino acid metabolism pathway.
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Leucemia , Humanos , Leucemia/metabolismo , Leucemia/tratamiento farmacológico , Leucemia/genética , Azufre/metabolismo , Animales , Aminoácidos/metabolismo , Aminoácidos Sulfúricos/metabolismo , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
BACKGROUND: Bleeding is a primary outcome for many transfusion-related trials in acute leukaemia (AL) patients, typically graded using the World Health Organisation (WHO) bleeding scale (clinically significant bleed (CSB) is ≥grade 2). This composite outcome fails to differentiate minor bleeds that may not be significant, poorly represents the total burden of bleeding and lacks input from healthcare providers (HCPs) and patients. As part of a multi-step project to create a better bleeding tool for trials, our objective was to identify HCPs' perspectives on the components of CSB in AL patients. STUDY DESIGN AND METHODS: Using qualitative description, we interviewed 19 physicians and nurses who care for AL patients undergoing induction chemotherapy. Participants were recruited from professional organisations, networks and social media. An inductive approach to conventional content analysis was used. RESULTS: HCPs identified features of CSB as the anatomical site of bleeding, amount of bleeding, need for intervention and changes in vital signs. Using these characteristics, bleeding events were categorised into three groups: clinically significant, could evolve into a CSB and not clinically significant. HCPs considered the patient's condition, bleeding history and clinical intuitions when deciding whether a bleed could escalate into serious bleeding. DISCUSSION: Using data from HCPs, we categorised bleeds as clinically significant, could evolve into a CSB, and not significant. A study of patients' perspectives on the importance of different kinds of bleeding is the next step to creating a bleeding definition that is informed by evidence, clinicians and patients.
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Hemorragia , Humanos , Hemorragia/inducido químicamente , Masculino , Femenino , Quimioterapia de Inducción , Investigación Cualitativa , Persona de Mediana Edad , Adulto , Leucemia/terapia , Leucemia/tratamiento farmacológico , Personal de Salud/psicologíaRESUMEN
BACKGROUND: Acute Myeloid Leukemia (AML) is a fast-developing invading cancer that impacts the blood and bone marrow, marked by the rapid proliferation of abnormal white blood cells. Chemotherapeutic agents, a primary treatment for AML, encounter clinical limitations such as poor solubility and low bioavailability. Previous studies have highlighted antibiotics as effective in inducing cancer cell death and potentially preventing metastasis. Besides, insulin is known to activate the PI3K/Akt pathway, often disrupted in cancers, leading to enhanced cell survival and resistance to apoptosis. In light of the above-mentioned points, we examined the anti-cancer impact of antibiotics Ciprofloxacin (CP) and Salinomycin (SAL) and their combination on KG1-a cells in the presence and absence of insulin. METHODS: This was accomplished by exposing KG1-a cells to different doses of CP and SAL alone, in combination, and with or without insulin for 24-72 h. Cell viability was evaluated using the MTT assay. Besides, apoptotic effects were examined using Hoechst staining and Annexin-V/PI flow cytometry. The expression levels of Bax, p53, BIRC5, Akt, PTEN, and FOXO1 were analyzed through Real-Time PCR. RESULTS: CP and SAL demonstrated cytotoxic and notable pro-apoptotic impact on KG1-a cells by upregulating Bax and p53 and downregulating BIRC5, leading to G0/G1 cell cycle arrest and prevention of the PI3K-Akt signaling pathway. Our findings demonstrated that combination of CP and SAL promote apoptosis in the KG1-a cell line by down-regulating BIRC5 and Akt, as well as up-regulating Bax, p53, PTEN, and FOXO1. Additionally, the findings strongly indicated that insulin effectively mitigates apoptosis by enhancing Akt expression and reducing FOXO1 and PTEN gene expression in the cells treated with CP and SAL. CONCLUSION: Our findings showed that the combined treatment of CP and SAL exhibit a strong anti-cancer effect on leukemia KG1-a cells. Moreover, it was discovered that the PI3K-Akt signaling can be a promising target in leukemia treatment particularly in hyperinsulinemia condition.