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1.
Cancer Cell ; 42(4): 552-567.e6, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38593781

RESUMEN

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.


Asunto(s)
Leucemia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Asparaginasa/farmacología , Farmacología en Red , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transducción de Señal , Leucemia/tratamiento farmacológico
2.
Eur J Med Res ; 29(1): 224, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38594732

RESUMEN

The latest findings in iron metabolism and the newly uncovered process of ferroptosis have paved the way for new potential strategies in anti-leukemia treatments. In the current project, we reviewed and summarized the current role of nanomedicine in the treatment and diagnosis of leukemia through a comparison made between traditional approaches applied in the treatment and diagnosis of leukemia via the existing investigations about the ferroptosis molecular mechanisms involved in various anti-tumor treatments. The application of nanotechnology and other novel technologies may provide a new direction in ferroptosis-driven leukemia therapies. The article explores the potential of targeting ferroptosis, a new form of regulated cell death, as a new therapeutic strategy for leukemia. It discusses the mechanisms of ferroptosis and its role in leukemia and how nanotechnology can enhance the delivery and efficacy of ferroptosis-inducing agents. The article not only highlights the promise of ferroptosis-targeted therapies and nanotechnology in revolutionizing leukemia treatment, but also calls for further research to overcome challenges and fully realize the clinical potential of this innovative approach. Finally, it discusses the challenges and opportunities in clinical applications of ferroptosis.


Asunto(s)
Ferroptosis , Leucemia , Humanos , Nanotecnología , Leucemia/tratamiento farmacológico
3.
Med Oncol ; 41(5): 113, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38602586

RESUMEN

Leukemia is a malignant disease of the hematopoietic system, in which clonal leukemia cells accumulate and inhibit normal hematopoiesis in the bone marrow and other hematopoietic tissues as a result of uncontrolled proliferation and impaired apoptosis, among other mechanisms. In this study, the anti-leukemic effect of a compound (SGP-17-S) extracted from Chloranthus multistachys, a plant with anti-inflammatory, antibacterial and anti-tumor effects, was evaluated. The effect of SGP-17-S on the viability of leukemic cell was demonstrated by MTT assay, cell cycle, and apoptosis were assessed by flow cytometry using PI staining and Annexin V/PI double staining. Combinations of network pharmacology and cellular thermal shift assay (CETSA) with western blot were used to validate agents that act on leukemia targets. The results showed that SGP-17-S inhibited the growth of leukemia cells in a time- and dose-dependent manner. SGP-17-S blocked HEL cells in the G2 phase, induced apoptosis, decreased Bcl-2 and caspase-8 protein expression, and increased Bax and caspase-3 expression. In addition, CETSA revealed that PARP1 is an important target gene for the inhibition of HEL cell growth, and SGP-17-S exerted its action on leukemia cells by targeting PARP1. Therefore, this study might provide new solutions and ideas for the treatment of leukemia.


Asunto(s)
Leucemia , Humanos , Leucemia/tratamiento farmacológico , Ciclo Celular , Proliferación Celular , División Celular , Anexina A5 , Poli(ADP-Ribosa) Polimerasa-1
4.
Cell Death Differ ; 31(4): 405-416, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38538744

RESUMEN

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLXL inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLXL. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Compuestos de Anilina , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Pirimidinas , Sulfonamidas , Proteína bcl-X , Humanos , Animales , Compuestos de Anilina/farmacología , Sulfonamidas/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Ratones , Proteína bcl-X/metabolismo , Proteína bcl-X/antagonistas & inhibidores , Línea Celular Tumoral , Pirimidinas/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Pirazoles/farmacología , Proteína Letal Asociada a bcl/metabolismo , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia/metabolismo , Fosforilación/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Sinergismo Farmacológico
5.
Int J Pharm ; 654: 123971, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38452832

RESUMEN

Lymphoma and leukemia are both hematological system tumors with complex etiology, and mainly treated with chemotherapeutic drugs. However, therapeutic drugs can interrupt curative effect due to different side effects. Therefore, it is worthwhile to develop a novel therapeutic for providing insights for clinical tumor treatment. In this study, we developed a fisetin nanoparticles (Fisetin NPs) through a self-assembled method, and investigated the activity and potential mechanism of Fisetin NPs against lymphoma and leukemia. The spherical and uniformly distributed Fisetin NPs effectively inhibited both tumor cells proliferation, arrested EL4 cells G0/G1 phase and K562 cells G2/M phase, and induced apoptosis in vitro. In vivo, Fisetin NPs exhibited excellent tumor growth inhibition, effective inhibition of cell proliferation and angiogenesis, significant induction of apoptosis and ideal safety. Mechanically, fisetin upregulated genes (Fas, Pidd, Puma, Apaf1, and p21) in the p53 signaling pathway and bound to N-acetyltransferase 10 (NAT10), ribosomal protein L34 (RPL34) and GTP binding protein 4 (GTPBP4). Collectively, Fisetin NPs have promising therapeutic effects on lymphoma and leukemia, which are of great significant for clinical implications.


Asunto(s)
Leucemia , Linfoma , Humanos , Flavonoides/farmacología , Flavonoles/farmacología , Apoptosis , Proliferación Celular , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Línea Celular Tumoral , Proteínas Nucleares/farmacología , Proteínas de Unión al GTP/farmacología , Acetiltransferasas N-Terminal
6.
Bioorg Chem ; 146: 107284, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38493640

RESUMEN

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, a novel series of easy-to-synthesize benzimidazole-linked (thio)hydantoin derivatives was designed and synthesized as HDAC6 inhibitors. All target compounds potently inhibited HDAC6 at nanomolar levels with compounds 2c, 2d, 4b and 4c (IC50s = 51.84-74.36 nM) being more potent than SAHA reference drug (IC50 = 91.73 nM). Additionally, the most potent derivatives were further assessed for their in vitro cytotoxic activity against two human leukemia cells. Hydantoin derivative 4c was equipotent/superior to SAHA against MOLT-4/CCRF-CEM leukemia cells, respectively and demonstrated safety profile better than that of SAHA against non-cancerous human cells. 4c was also screened against different HDAC isoforms. 4c was superior to SAHA against HDAC1. Cell-based assessment of 4c revealed a significant cell cycle arrest and apoptosis induction. Moreover, western blotting analysis showed increased levels of acetylated histone H3, histone H4 and α-tubulin in CCRF-CEM cells. Furthermore, docking study exposed the ability of title compounds to chelate Zn2+ located within HDAC6 active site. As well, in-silico evaluation of physicochemical properties showed that target compounds are promising candidates in terms of pharmacokinetic aspects.


Asunto(s)
Antineoplásicos , Hidantoínas , Leucemia , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Relación Estructura-Actividad , Hidantoínas/farmacología , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/química , Histona Desacetilasas/metabolismo , Línea Celular Tumoral , Histonas/metabolismo , Leucemia/tratamiento farmacológico , Zinc/metabolismo , Simulación del Acoplamiento Molecular
7.
Support Care Cancer ; 32(3): 207, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38436749

RESUMEN

PURPOSE: Children with leukemia may experience a range of chemotherapy-related symptoms. Identifying subgroups and their distinct characteristics of symptoms may improve symptom management. We aimed to identify subgroups and their distinct characteristics of chemotherapy-related symptoms in children with leukemia. METHODS: A cross-sectional survey was conducted among 500 children with leukemia, who completed questionnaires that assessed their demographic and clinical characteristics, as well as the Memorial Symptom Assessment Scale. Latent profile analysis was conducted to identify subgroups of symptoms. Additionally, multiple regression analysis and network analysis were utilized to reveal the characteristics of each subgroup. RESULTS: Four subgroups were identified: "Profile 1: low symptom burden subgroup" (26.2%), "Profile 2: moderate symptom burden subgroup in transitional period" (14.8%), "Profile 3: moderate psychological symptom burden subgroup" (35.6%), and "Profile 4: high symptom burden subgroup" (23.4%). Multiple logistic regression analysis indicated that lower primary caregiver's education level, lower family monthly income, self-paid medical expenses, induction remission period, and consolidation enhancement period were associated with more severe symptoms of subgroups. Network analysis further revealed that nausea was the core symptom in Profiles 1 and 2, while the core symptom in Profile 3 was "I don't look like myself." Additionally, worrying was the core symptom in Profile 4. CONCLUSION: There exists heterogeneity in chemotherapy-related symptoms. Four subgroups and their corresponding characteristics of children with varying symptom severity were identified. Identifying these subgroups will facilitate personalized care, maximize intervention effectiveness, and alleviate symptom burden.


Asunto(s)
Leucemia , Niño , Humanos , Estudios Transversales , Leucemia/tratamiento farmacológico , Escolaridad , Renta , Náusea
8.
Int J Mol Sci ; 25(6)2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38542061

RESUMEN

Naphthylisoquinoline (NIQ) alkaloids are rising as a promising class of secondary metabolites with pharmaceutical potential. NF-κB has already been recognized as a significant modulator of cancer proliferation and drug resistance. We have previously reported the mechanisms behind the cytotoxic effect of dioncophylline A, an NIQ monomer, in leukemia cells. In the current study, we have investigated the cytotoxic effect of jozimine A2, an NIQ dimer, on leukemia cells in comparison to a second, structurally unsymmetric dimer, michellamine B. To this end, molecular docking was applied to predict the binding affinity of the dimers towards NF-κB, which was then validated through microscale thermophoresis. Next, cytotoxicity assays were performed on CCRF-CEM cells and multidrug-resistant CEM/ADR5000 cells following treatment. Transcriptome analysis uncovered the molecular networks affected by jozimine A2 and identified the cell cycle as one of the major affected processes. Cell death modes were evaluated through flow cytometry, while angiogenesis was measured with the endothelial cell tube formation assay on human umbilical vein endothelial cells (HUVECs). The results indicated that jozimine A2 bound to NF-κB, inhibited its activity and prevented its translocation to the nucleus. In addition, jozimine A2 induced cell death through apoptosis and prevented angiogenesis. Our study describes the cytotoxic effect of jozimine A2 on leukemia cells and explains the interactions with the NF-κB signaling pathway and the anticancer activity.


Asunto(s)
Alcaloides , Antineoplásicos , Leucemia , Humanos , Alcaloides/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Resistencia a Antineoplásicos , Células Endoteliales , Leucemia/tratamiento farmacológico , Simulación del Acoplamiento Molecular , FN-kappa B/farmacología
9.
Anticancer Res ; 44(3): 981-991, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38423659

RESUMEN

BACKGROUND/AIM: Methionine metabolism contributes to supplying sulfur-containing amino acids, controlling the methyl group transfer reaction, and producing polyamines in cancer cells. Polyamines play important roles in various cellular functions. Methylthioadenosine phosphorylase (MTAP), the key enzyme of the methionine salvage pathway, is reported to be deficient in 15-62% of cases of hematological malignancies. MTAP-deficient cancer cells accumulate polyamines, resulting in enhanced cell proliferation. The aim of this study was to investigate the combined effects of the polyamine synthesis inhibitor SAM486A and the anticancer antimetabolite cytarabine in MTAP-deficient leukemic cells in vitro. MATERIALS AND METHODS: The leukemia cell line U937 and the subline, U937/MTAP(-), in which MTAP was knocked down by shRNA, were used. The experiments were performed in media supplemented with 20% methionine (low methionine), which was the minimum concentration for maintaining cellular viability. RESULTS: The knockdown efficiency test confirmed a 70% suppression of the expression of the MTAP gene in U937/MTAP(-) cells. Even in the media with low methionine, the intracellular methionine concentration was not reduced in U937/MTAP(-) cells, suggesting that the minimum supply of methionine was sufficient to maintain intracellular levels of methionine. Both U937/MTAP(+) and U937/MTAP(-) cells were comparably sensitive to anticancer drugs (cytarabine, methotrexate, clofarabine and 6-thioguanine). The combination of SAM486A and cytarabine was demonstrated to have synergistic cytotoxicity in U937/MTAP(-) cells with regard to cell growth inhibition and apoptosis induction, but not in U937/MTAP(+) cells. Mechanistically, SAM486A altered the intracellular polyamine concentrations and reduced the antiapoptotic proteins. CONCLUSION: Methionine metabolism and polyamine synthesis can be attractive therapeutic targets in leukemia.


Asunto(s)
Amidinas , Antineoplásicos , Indanos , Leucemia , Humanos , Citarabina/farmacología , Purina-Nucleósido Fosforilasa/genética , Purina-Nucleósido Fosforilasa/metabolismo , Poliaminas , Metionina/farmacología , Metionina/metabolismo , Leucemia/tratamiento farmacológico
10.
Eur J Med Chem ; 268: 116226, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38367493

RESUMEN

To interfere the Menin-MLL interaction using small molecular inhibitors has been shown as new treatment of several special hematological malignancies. Herein, a series of Menin-MLL interaction inhibitors with pyrrolo[2,3-d]pyrimidine scaffold were designed, synthesized and evaluated. Among them, compound A6 exhibited potent binding affinity with an IC50 value of 0.38 µM, and strong anti-proliferative activity against MV4-11 cells with an IC50 value of 1.07 µM. Further study showed A6 reduced the transcriptional levels of HOXA9 and MEIS1 genes. Moreover, A6 induced cellular apoptosis, arrested the cell cycle in G0/G1 phase, and reversed the differentiation arrest in a concentration-dependent manner. This study suggested compound A6 was as a novel potent Menin-MLL interaction inhibitor, and it proved that introduction of 4-amino pyrrolo[2,3-d]pyrimidine to occupy the P10 hydrophobic pocket was new idea for design of novel Menin-MLL interaction inhibitors.


Asunto(s)
Leucemia , Proteína de la Leucemia Mieloide-Linfoide , Humanos , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Leucemia/tratamiento farmacológico , Pirimidinas/farmacología
11.
Clin Exp Pharmacol Physiol ; 51(4): e13847, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38382534

RESUMEN

The use of all-trans retinoic acid and arsenic trioxide resulted in favourable therapeutic responses in standard-risk acute promyelocytic leukaemia (APL) patients. However, resistance to these agents has made treating the high-risk subgroup more problematic, and possible side effects limit their clinical dosages. Numerous studies have proven the cytotoxic properties of Gaillardin, one of the Inula oculus-christi-derived sesquiterpene lactones. Due to the adverse effects of arsenic trioxide on the high-risk subgroup of APL patients, we aimed to assess the cytotoxic effect of Gaillardin on HL-60 cells as a single or combined-form approach. The results of the trypan blue and MTT assays outlined the potent cytotoxic properties of Gaillardin. The flow cytometric analysis and the mRNA expression levels revealed that Gaillardin attenuated the proliferative capacity of HL-60 cells through cell cycle arrest and induced apoptosis via reactive oxygen species generation. Moreover, the results of synergistic experiments indicated that this sesquiterpene lactone sensitizes HL-60 cells to the cytotoxic effects of arsenic trioxide. Taken together, the findings of the present investigation highlighted the antileukemic characteristics of Gaillardin by inducing G1 cell cycle arrest and triggering apoptosis. Gaillardin acts as an antileukemic metabolite against HL-60 cells and this study provides new insight into treating APL patients, especially in the high-risk subgroup.


Asunto(s)
Antineoplásicos , Leucemia , Sesquiterpenos , Humanos , Trióxido de Arsénico/farmacología , Células HL-60 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Lactonas/farmacología , Lactonas/uso terapéutico , Sesquiterpenos/farmacología , Sesquiterpenos/uso terapéutico , Leucemia/tratamiento farmacológico , Apoptosis , Óxidos/farmacología , Óxidos/uso terapéutico
12.
Cell Commun Signal ; 22(1): 105, 2024 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-38331801

RESUMEN

The current scientific literature has extensively explored the potential role of proteasome inhibitors (PIs) in the NF-κB pathway of leukemia and lymphoma. The ubiquitin-proteasome system (UPS) is a critical component in regulating protein degradation in eukaryotic cells. PIs, such as BTZ, are used to target the 26S proteasome in hematologic malignancies, resulting in the prevention of the degradation of tumor suppressor proteins, the activation of intrinsic mitochondrial-dependent cell death, and the inhibition of the NF-κB signaling pathway. NF-κB is a transcription factor that plays a critical role in the regulation of apoptosis, cell proliferation, differentiation, inflammation, angiogenesis, and tumor migration. Despite the successful use of PIs in various hematologic malignancies, there are limitations such as resistant to these inhibitors. Some reports suggest that PIs can induce NF-κB activation, which increases the survival of malignant cells. This article discusses the various aspects of PIs' effects on the NF-κB pathway and their limitations. Video Abstract.


Asunto(s)
Neoplasias Hematológicas , Leucemia , Linfoma , Humanos , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , FN-kappa B/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Apoptosis
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(1): 33-38, 2024 Feb.
Artículo en Chino | MEDLINE | ID: mdl-38387896

RESUMEN

OBJECTIVE: To explore the role of bone marrow mesenchymal stem cells (BMSC),an essential element of the bone marrow microenvironment, in multidrug resistance(MDR) of K562 cells, as well as the reversal effect of tetrandrine (TET) on BMSC-mediated MDR and its potential mechanism. METHODS: A mixed co-culture system and a transwell co-culture system for BMSC and K562 cells were established, and the cells were divided into different groups and treated with daunorubicin (DNR) alone or combined with TET and DNR. The CCK-8 assay was used to detect the proliferation of K562 cells in each group, and the cell inhibition rate was calculated. Cytometric bead array (CBA) was used to detect the expression levels of IFN, IL-2, IL-6 and IL-10 in the supernatant of different groups. RT-qPCR and Western blot were used to detected the expression of STAT3 at mRNA and protein levels, respectively. RESULTS: Compared with K562+DNR group, the inhibition rate of DNR on K562 cell proliferation in K562+BMSC+DNR group was significantly decreased (P < 0.05), while the levels of IL-6 in the culture supernatant and phosphorylated STAT3 in K562 cells were significantly increased (P < 0.05). Compared with K562+BMSC+DNR group, the inhibition rate of DNR on K562 cell proliferation in K562+BMSC+DNR+TET group was significantly increased (P < 0.05), while the level of IL-6 and phosphorylated STAT3 was significantly decreased (P < 0.05). CONCLUSION: BMSC can promote the drug resistance of leukemia cells, and TET may reverse the BMSC-mediated drug resistance via inhibiting IL-6/STAT3 signaling pathway.


Asunto(s)
Bencilisoquinolinas , Leucemia , Humanos , Interleucina-6 , Resistencia a Antineoplásicos , Bencilisoquinolinas/farmacología , Bencilisoquinolinas/uso terapéutico , Daunorrubicina/farmacología , Células K562 , Leucemia/tratamiento farmacológico , Microambiente Tumoral
14.
Int J Mol Sci ; 25(3)2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38339054

RESUMEN

Allogeneic haematopoietic stem cell transplantation (HSCT) leads to the establishment of graft-versus-leukaemia (GVL) immunity, but in many cases also results in the development of graft-versus-host disease (GVHD). This study aimed to determine if P2X7 antagonism using Brilliant Blue G (BBG) could improve the beneficial effects of post-transplant cyclophosphamide (PTCy) in a humanised mouse model of GVHD, without comprising GVL immunity. NOD.Cg-Prkdcscid Il2rgtm1Wjl (NSG) mice were injected with human peripheral blood mononuclear cells (PBMCs) (Day 0), then with cyclophosphamide (33 mg/kg) on Days 3 and 4, and with BBG (50 mg/kg) (or saline) on Days 0-10. PTCy with BBG reduced clinical GVHD development like that of PTCy alone. However, histological analysis revealed that the combined treatment reduced liver GVHD to a greater extent than PTCy alone. Flow cytometric analyses revealed that this reduction in liver GVHD by PTCy with BBG corresponded to an increase in human splenic CD39+ Tregs and a decrease in human serum interferon-γ concentrations. In additional experiments, humanised NSG mice, following combined treatment, were injected with human THP-1 acute myeloid leukaemia cells on Day 14. Flow cytometric analyses of liver CD33+ THP-1 cells showed that PTCy with BBG did not mitigate GVL immunity. In summary, PTCy combined with BBG can reduce GVHD without compromising GVL immunity. Future studies investigating P2X7 antagonism in combination with PTCy may lead to the development of novel treatments that more effectively reduce GVHD in allogeneic HSCT patients without promoting leukaemia relapse.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia , Colorantes de Rosanilina , Humanos , Animales , Ratones , Leucocitos Mononucleares , Ratones Endogámicos NOD , Recurrencia Local de Neoplasia/tratamiento farmacológico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Ciclofosfamida/uso terapéutico , Leucemia/tratamiento farmacológico , Estudios Retrospectivos
15.
J Mater Chem B ; 12(10): 2459-2470, 2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38345341

RESUMEN

Leukemia is a type of clonal disorder of hematopoietic stem and progenitor cells characterized by bone marrow failure, differentiation arrest, and lineage skewing. Despite leukemia being a complex disease and it being difficult to identify a single driving force, redox homeostasis, the balance between reactive oxygen species (ROS) producers and cellular antioxidant systems, is normally impaired during leukemogenesis. In this context, the modulation of ROS in leukemia cells can be harnessed for therapeutic purposes. Nanozymes are functional nanomaterials with enzyme-like characteristics, which address the intrinsic limitations of natural enzymes and exhibit great potential in synergistic antitumor therapy. Nanozymes possess catalytic activities (e.g., peroxidase-like activity, catalase-like activity, superoxide dismutase-like activity, and oxidase-like activity) to regulate ROS levels in vitro and in vivo, making them promising for leukemia therapy. On account of the rapid development of nanozymes recently, their application potentials in leukemia therapy are gradually being explored. To highlight the achievements of nanozymes in the leukemia field, this review summarizes the recent studies of nanozymes with anti-leukemia efficacy and the underlying mechanism. In addition, the challenges and prospects of nanozyme research in leukemia therapy are discussed.


Asunto(s)
Leucemia , Nanoestructuras , Humanos , Catálisis , Especies Reactivas de Oxígeno , Nanoestructuras/uso terapéutico , Oxidación-Reducción , Leucemia/tratamiento farmacológico
16.
Sci Adv ; 10(8): eadk3127, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38394203

RESUMEN

Epigenetic dysregulation has been reported in multiple cancers including leukemias. Nonetheless, the roles of the epigenetic reader Tudor domains in leukemia progression and therapy remain unexplored. Here, we conducted a Tudor domain-focused CRISPR screen and identified SGF29, a component of SAGA/ATAC acetyltransferase complexes, as a crucial factor for H3K9 acetylation, ribosomal gene expression, and leukemogenesis. To facilitate drug development, we integrated the CRISPR tiling scan with compound docking and molecular dynamics simulation, presenting a generally applicable strategy called CRISPR-Scan Assisted Drug Discovery (CRISPR-SADD). Using this approach, we identified a lead inhibitor that selectively targets SGF29's Tudor domain and demonstrates efficacy against leukemia. Furthermore, we propose that the structural genetics approach used in our study can be widely applied to diverse fields for de novo drug discovery.


Asunto(s)
Leucemia , Dominio Tudor , Humanos , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Acetiltransferasas/metabolismo , Descubrimiento de Drogas , Leucemia/tratamiento farmacológico , Leucemia/genética
17.
Microb Cell Fact ; 23(1): 51, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38355518

RESUMEN

BACKGROUND: In hematologic cancers, including leukemia, cells depend on amino acids for rapid growth. Anti-metabolites that prevent their synthesis or promote their degradation are considered potential cancer treatment agents. Amino acid deprivation triggers proliferation inhibition, autophagy, and programmed cell death. L-lysine, an essential amino acid, is required for tumor growth and has been investigated for its potential as a target for cancer treatment. L-lysine α-oxidase, a flavoenzyme that degrades L-lysine, has been studied for its ability to induce apoptosis and prevent cancer cell proliferation. In this study, we describe the use of L-lysine α-oxidase (LO) from the filamentous fungus Trichoderma harzianum for cancer treatment. RESULTS: The study identified and characterized a novel LO from T. harzianum and demonstrated that the recombinant protein (rLO) has potent and selective cytotoxic effects on leukemic cells by triggering the apoptotic cascade through mitochondrial dysfunction. CONCLUSIONS: The results support future translational studies using the recombinant LO as a potential drug for the treatment of leukemia.


Asunto(s)
Hypocreales , Leucemia , Neoplasias , Trichoderma , Humanos , Lisina , Apoptosis , Leucemia/tratamiento farmacológico , Necrosis
19.
J Ethnopharmacol ; 325: 117847, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38307357

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. has been used in traditional Russian medicine due to its recognized immunostimulant and anti-inflammatory activities. Compounds present in the fruits have demonstrated the capability to modulate the activity of enzymes such as hyaluronidase, suggesting their potential value in the development of effective therapies for various conditions where anti-inflammatory properties are beneficial, such as gastrointestinal diseases and tumor growth. AIM OF THE STUDY: In order to support the use of the fruits in folk medicine, this study is aimed to evaluate, post-mortem, the impact of E. senticosus fruits intractum (40 % extract made from fresh fruits) on the transepithelial electrogenic transport of sodium ions in the colon. The objective of this study was also to examine the impact of the intractum on proinflammatory serum hyaluronidase in children diagnosed with acute leukemia. METHODS: The study employed the Ussing technique to examine electrophysiological characteristics of isolated epithelial tissue, using the distal colon wall isolated from 10 New Zealand white male rabbits. The effect of the intractum on the inhibition of human serum hyaluronidase was examined with turbidimetric screening methods, using the blood samples collected from patients diagnosed with acute leukemia. RESULTS: For the first time, we discovered that the intractum used in the stimulation fluid, caused hyperpolarization reactions in colon tissue. Statistical analysis showed that these reactions were significantly different in relation to the control. The intractum significantly inhibited hyaluronidase activity with the mean value by group of 60 %, and 40 % for aescin used as a control. CONCLUSION: The results support the traditional use of the fruits in inflammatory-related diseases. The use of intractum of E. senticosus on the distal colon wall demonstrates its protective effect on the wall integrity and in a relation to hyaluronidase inhibition may additionally indicate its anti-inflammatory property. Thus, the results mean that the intractum may be used in colon-related diseases.


Asunto(s)
Eleutherococcus , Leucemia , Niño , Humanos , Masculino , Conejos , Animales , Extractos Vegetales/uso terapéutico , Frutas/química , Hialuronoglucosaminidasa , Intestino Grueso , Leucemia/tratamiento farmacológico , Antiinflamatorios/farmacología
20.
Nutr Cancer ; 76(3): 236-251, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38263604

RESUMEN

Leukemia is a heterogeneous clonal cancer that affects millions of individuals around the world. Despite substantial breakthroughs in cancer treatment, traditional chemotherapy and radiotherapy remain ineffective, and therapeutic resistance still stands as a big obstacle. As a result, there is an increasing attention being paid currently toward the potency of natural compounds as a complementary or alternative therapy for leukemia. Autophagy, a conserved cellular process where damaged or defective cytosolic components and macromolecules are destroyed and recycled, plays a dual role in promoting or suppressing the continuance of cancer at different junctures of its development. Current studies have reported that autophagy has a cardinal function in the genesis and progression of leukemia, making it a promising target for novel treatments. In this review, we have explored the effectiveness of certain natural compounds, such as curcumin, resveratrol, tanshinone IIA, quercetin, tetrandrine, parthenolide, berberine, pristimerin, and alantolactone, that modulate autophagy and regulate its associated signaling cascades at a molecular level in different types of leukemia. They have been shown to have synergistic effects with conventional chemotherapy, emphasizing their potential as supplementary medicines. However, additional research is required to fully comprehend their mechanisms of action and to maximize their role in clinical perspectives.


Asunto(s)
Leucemia , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Leucemia/tratamiento farmacológico , Transducción de Señal , Resveratrol/farmacología , Autofagia
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