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1.
Biomed Pharmacother ; 139: 111656, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243603

RESUMO

INTRODUCTION: Amyrins are triterpenes that have attractive pharmacological potential; however, their low water solubility and erratic stomach absorption hinders their use as a drug. The aim of this paper was to develop a novel α-amyrin-loaded nanocapsule for intestinal delivery and evaluate, preliminarily, its cytotoxic ability against leukemic cells. MATERIAL AND METHODS: Five nanocapsule formulations were designed by the solvent displacement-evaporation method. Poly-ε-caprolactone, Eudragit® E100, and Kollicoat® Mae 100 P were used as film-former materials. Particle size, polydispersity index (PdI), zeta potential, and the pH of all formulations were measured. The cytotoxic potential of the nanocapsules was evaluated in vitro using different leukemic lineages RESULTS: Nanocapsules coated with Kollicoat® Mae 100 P presented the smallest particle size (130 nm), the lowest zeta-potential (-38 mV), and the narrowest size distribution (PdI = 0.100). The entrapment efficiency was 65.47%, while the loading capacity was 2.40%. Nanocapsules release 100% of α-amyrin in 40 min (pH 7.4), by using a possible mechanism of swelling-diffusion. The formulation showed excellent on-shelf physicochemical stability during one year. Additionally, nanocapsules produced a selective cytotoxic effect on a human leukemia lineage Kasumi-1, an acute myeloid leukemia cell line, and produced cell death by apoptosis CONCLUSION: α-amyrin-loaded nanocapsules appear to be a promising nanoformulation that could be used against leukemia.


Assuntos
Leucemia/tratamento farmacológico , Nanocápsulas/química , Triterpenos Pentacíclicos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caproatos/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Células Jurkat , Células K562 , Lactonas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Tamanho da Partícula , Ácidos Polimetacrílicos/química
2.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206957

RESUMO

In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are common due to the survival mechanisms utilised by leukaemic cells. One such mechanism is through hijacking of the bone marrow microenvironment, where healthy haematopoietic machinery is transformed or remodelled into a hiding ground or "sanctuary" where leukaemic cells can escape chemotherapy-induced cytotoxicity. The bone marrow microenvironment, which consists of endosteal and vascular niches, can support leukaemogenesis through intercellular "crosstalk" with niche cells, including mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts. Here, we summarise the regulatory mechanisms associated with leukaemia-bone marrow niche interaction and provide a comprehensive review of the key therapeutics that target CXCL12/CXCR4, Notch, Wnt/b-catenin, and hypoxia-related signalling pathways within the leukaemic niches and agents involved in remodelling of niche bone and vasculature. From a therapeutic perspective, targeting these cellular interactions is an exciting novel strategy for enhancing treatment efficacy, and further clinical application has significant potential to improve the outcome of patients with leukaemia.


Assuntos
Leucemia/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Humanos , Leucemia/patologia , Transdução de Sinais
3.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202812

RESUMO

The endocannabinoid system (ECS) is a composite cell-signaling system that allows endogenous cannabinoid ligands to control cell functions through the interaction with cannabinoid receptors. Modifications of the ECS might contribute to the pathogenesis of different diseases, including cancers. However, the use of these compounds as antitumor agents remains debatable. Pre-clinical experimental studies have shown that cannabinoids (CBs) might be effective for the treatment of hematological malignancies, such as leukemia and lymphoma. Specifically, CBs may activate programmed cell death mechanisms, thus blocking cancer cell growth, and may modulate both autophagy and angiogenesis. Therefore, CBs may have significant anti-tumor effects in hematologic diseases and may synergistically act with chemotherapeutic agents, possibly also reducing chemoresistance. Moreover, targeting ECS might be considered as a novel approach for the management of graft versus host disease, thus reducing some symptoms such as anorexia, cachexia, fatigue, anxiety, depression, and neuropathic pain. The aim of the present review is to collect the state of the art of CBs effects on hematological tumors, thus focusing on the essential topics that might be useful before moving into the clinical practice.


Assuntos
Canabinoides/uso terapêutico , Neoplasias Hematológicas , Proteínas de Neoplasias/metabolismo , Receptores de Canabinoides/metabolismo , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Linfoma/tratamento farmacológico , Linfoma/metabolismo , Linfoma/patologia
4.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063044

RESUMO

The use of biologically active compounds has become a realistic option for the treatment of malignant tumors due to their cost-effectiveness and safety. In this review, we aimed to highlight the main natural biocompounds that target leukemic cells, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their therapeutic potential in the treatment of leukemia: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). It provides a basis for researchers and hematologists in improving basic and clinical research on the development of new alternative therapies in the fight against leukemia, a harmful hematological cancer and the leading cause of death among patients.


Assuntos
Antineoplásicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Leucemia/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Ensaios Clínicos como Assunto , Sinergismo Farmacológico , Humanos
5.
Molecules ; 26(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066963

RESUMO

Leukemia is a leukocyte cancer that is characterized by anarchic growth of immature immune cells in the bone marrow, blood and spleen. There are many forms of leukemia, and the best course of therapy and the chance of a patient's survival depend on the type of leukemic disease. Different forms of drugs have been used to treat leukemia. Due to the adverse effects associated with such therapies and drug resistance, the search for safer and more effective drugs remains one of the most challenging areas of research. Thus, new therapeutic approaches are important to improving outcomes. Almost half of the drugs utilized nowadays in treating cancer are from natural products and their derivatives. Medicinal plants have proven to be an effective natural source of anti-leukemic drugs. The cytotoxicity and the mechanisms underlying the toxicity of these plants to leukemic cells and their isolated compounds were investigated. Effort has been made throughout this comprehensive review to highlight the recent developments and milestones achieved in leukemia therapies using plant-derived compounds and the crude extracts from various medicinal plants. Furthermore, the mechanisms of action of these plants are discussed.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Leucemia/tratamento farmacológico , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Humanos
6.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072126

RESUMO

The biological activities of shancigusin C (1) and bletistrin G (2), natural products isolated from orchids, are reported along with their first total syntheses. The total synthesis of shancigusin C (1) was conducted by employing the Perkin reaction to forge the central stilbene core, whereas the synthesis of bletistrin G (2) was achieved by the Wittig olefination followed by several regioselective aromatic substitution reactions. Both syntheses were completed by applying only renewable starting materials according to the principles of xylochemistry. The cytotoxic properties of shancigusin C (1) and bletistrin G (2) against tumor cells suggest suitability as a starting point for further structural variation.


Assuntos
Produtos Biológicos/farmacologia , Resistência a Múltiplos Medicamentos , Orchidaceae , Extratos Vegetais/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Química Farmacêutica/métodos , Di-Hidroestilbenoides/química , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Estereoisomerismo , Estilbenos/química
7.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072627

RESUMO

BACKGROUND: Glucocorticoids play an essential part in anti-leukemic therapies, but resistance is a crucial event for the prognosis of the disease. Glucocorticoids influence the metabolic properties of leukemic cells. The inherent plasticity of clinically evolving cancer cells justifies the characterization of drug-induced early oncogenic pathways, which represent a likely source of detrimental secondary effects. AIM: The present work aims to investigate the effect of glucocorticoids in metabolic pathways in the CCRF-CEM leukemic cells. Metabolic factors and gene expression profiles were examined in order to unravel the possible mechanisms of the CCRF-CEM leukemic cell growth dynamics. METHODS: CCRF-CEM cells were used as a model. Cells were treated with prednisolone with concentrations 0-700 µM. Cell culture supernatants were used for glucose, lactic acid, LDH, Na+, K+ and Ca++ measurements. Cytotoxicity was determined with flow cytometry. Microarray analysis was performed using two different chips of 1.2 k and 4.8 k genes. Gene Ontology enrichment analysis was applied to find metabolism- and GC-related genes. RESULTS: Higher prednisolone concentrations inhibited glucose uptake, without exhibiting any cytotoxic effects. Glucose consumption did not correlate with the total cell population, or the viable population, indicating that growth is not directly proportional to glucose consumption. Neither of the subpopulations, i.e., viable, necrotic, or apoptotic cells, contributed to this. CONCLUSIONS: Different types of leukemic cells seem to exhibit different patterns of glucose metabolism. Both resistant and sensitive CCRF-CEM cells followed the aerobic pathway of glycolysis. There is probably a rapid change in membrane permeability, causing a general shutdown towards everything that is outside the cell. This could in part also explain the observed resistance. Glucocorticoids do not enter the cell passively anymore and therefore no effects are observed. Based on our observations, ion concentrations are measurable factors both in vitro and in vivo, which makes them possible markers of glucocorticoid cytotoxic action.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Leucemia/genética , Leucemia/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Glucocorticoides/uso terapêutico , Glicólise , Humanos , Leucemia/tratamento farmacológico , Leucemia/patologia , Prednisolona/farmacologia , Transcriptoma , Células Tumorais Cultivadas
8.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067305

RESUMO

Leukemia is persistently a significant cause of illness and mortality worldwide. Urolithins, metabolites of ellagic acid and ellagitannins produced by gut microbiota, showed better bioactive compounds liable for the health benefits exerted by ellagic acid and ellagitannins containing pomegranate and walnuts. Here, we assessed the potential antileukemic activities of both urolithin A and urolithin B. Results showed that both urolithin A and B significantly inhibited the proliferation of leukemic cell lines Jurkat and K562, among which urolithin A showed the more prominent antiproliferative capability. Further, urolithin treatment alters leukemic cell metabolism, as evidenced by increased metabolic rate and notable changes in glutamine metabolism, one-carbon metabolism, and lipid metabolism. Next, we evidenced that both urolithins equally promoted apoptosis in leukemic cell lines. Based on these observations, we concluded that both urolithin A and B alter leukemic cell metabolome, resulting in a halt of proliferation, followed by apoptosis. The data can be used for designing new combinational therapies to eradicate leukemic cells.


Assuntos
Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Leucemia/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ácido Elágico/farmacologia , Frutas/química , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Taninos Hidrolisáveis/farmacologia , Juglans/química , Células Jurkat , Células K562 , Metabolismo dos Lipídeos/efeitos dos fármacos , Nozes/química , Romã (Fruta)/química
9.
Nat Commun ; 12(1): 2792, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990599

RESUMO

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Leucemia/tratamento farmacológico , Leucemia/enzimologia , Animais , Antineoplásicos/química , Domínio Catalítico/efeitos dos fármacos , Domínio Catalítico/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Cristalografia por Raios X , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Desenho de Fármacos , Descoberta de Drogas , Inibidores Enzimáticos/química , Feminino , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Humanos , Leucemia/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Proteína de Leucina Linfoide-Mieloide/genética , Oncogenes , Domínios Proteicos , Proteínas Recombinantes de Fusão/genética
10.
J Med Chem ; 64(11): 7179-7188, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34014084

RESUMO

Over the past decades, therapeutics based on biological macromolecules and cells have successfully entered the clinical arena and progressively occupied an increasing share of what once was almost exclusively small molecule territory. This perspective explores the opportunities for chemists at the interface between biologics and small molecule-based products. It provides concrete examples by zooming in on the area of post-translational protein modification. The conclusion is that, rather than diminishing the relevance of chemistry in the pharmaceutical enterprise, the advent of the biologics has provided an additional playing field for synthetic and medicinal chemists, where they can contribute to the efficacy and scope of applicability of biological entities in a collaborative effort to transformatively address unmet medical needs.


Assuntos
Química Farmacêutica , Proteínas/química , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Humanos , Imunoconjugados/química , Imunoconjugados/metabolismo , Imunoconjugados/uso terapêutico , Leucemia/tratamento farmacológico , Processamento de Proteína Pós-Traducional , Proteínas/imunologia , Proteínas/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
11.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802972

RESUMO

Leukaemia is a malignant disease of the blood. Current treatments for leukaemia are associated with serious side-effects. Plant-derived polyphenols have been identified as potent anti-cancer agents and have been shown to work synergistically with standard chemotherapy agents in leukaemia cell lines. Polyphenols have multiple mechanisms of action and have been reported to decrease cell proliferation, arrest cell cycle and induce apoptosis via the activation of caspase (3, 8 and 9); the loss of mitochondrial membrane potential and the release of cytochrome c. Polyphenols have been shown to suppress activation of transcription factors, including NF-kB and STAT3. Furthermore, polyphenols have pro-oxidant properties, with increasing evidence that polyphenols inhibit the antioxidant activity of glutathione, causing oxidative DNA damage. Polyphenols also induce autophagy-driven cancer cell death and regulate multidrug resistance proteins, and thus may be able to reverse resistance to chemotherapy agents. This review examines the molecular mechanism of action of polyphenols and discusses their potential therapeutic targets. Here, we discuss the pharmacological properties of polyphenols, including their anti-inflammatory, antioxidant, anti-proliferative, and anti-tumour activities, and suggest that polyphenols are potent natural agents that can be useful therapeutically; and discuss why data on bioavailability, toxicity and metabolism are essential to evaluate their clinical use.


Assuntos
Leucemia/tratamento farmacológico , Polifenóis/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Humanos , Leucemia/patologia , Modelos Biológicos , Polifenóis/química , Polifenóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo
12.
Int J Mol Sci ; 22(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919224

RESUMO

Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels-Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs.


Assuntos
Apoptose , Leucemia/tratamento farmacológico , Transdução de Sinais , Succinimidas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Células Cultivadas , Células Endoteliais , Feminino , Células HeLa , Humanos , Células K562 , Leucemia/metabolismo , Leucemia/fisiopatologia , MAP Quinase Quinase Quinases , Proteínas Quinases/metabolismo , Succinimidas/síntese química , Succinimidas/uso terapêutico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/fisiopatologia
13.
Chemistry ; 27(33): 8590-8599, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-33851760

RESUMO

Specific sensing and functional tuning of nucleic acid secondary structures remain less explored to date. Herein, we report a thiazole polyamide TPW that binds specifically to c-KIT1 G-quadruplex (G4) with sub-micromolar affinity and ∼1 : 1 stoichiometry and represses c-KIT proto-oncogene expression. TPW shows up to 10-fold increase in fluorescence upon binding with c-KIT1 G4, but shows weak or no quantifiable binding to other G4s and ds26 DNA. TPW can increase the number of G4-specific antibody (BG4) foci and mark G4 structures in cancer cells. Cell-based assays reveal that TPW can efficiently repress c-KIT expression in leukemia cells via a G4-dependent process. Thus, the polyamide can serve as a promising probe for G-quadruplex recognition with the ability to specifically alter c-KIT oncogene expression.


Assuntos
Quadruplex G , Leucemia , Humanos , Leucemia/tratamento farmacológico , Ligantes , Nylons , Regiões Promotoras Genéticas , Tiazóis
14.
Mar Drugs ; 19(3)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801204

RESUMO

Our previous studies have found that (±)-(E)-12-hydroxyoctadec-10-enoic acid (HOEA) isolated from the red alga Tricleocarpa jejuensis showed cytotoxic effects on various living organisms including harmful microalgae, Gram-positive bacteria, and mammalian tumor cells. Since natural products with apoptosis-inducing ability can be promising anti-cancer agents, in this study, we investigated the cytotoxic mechanism of HOEA on U937 cells focusing on apoptosis induction. HOEA showed much stronger cytotoxic and cytolytic effects on U937 cells than elaidic acid, which has similar structure but no 12-hydroxy group, suggesting that hydroxy group is important for the cytotoxicity of HOEA. HOEA induced apoptotic nuclear morphological changes, DNA fragmentation, and decrease in mitochondrial membrane potential. Furthermore, time-dependent increase in annexin V+/PI+ cell population in HOEA-treated U937 cells was detected. Among the apoptosis-related reagents, caspase-family inhibitor almost completely inhibited HOEA-induced DNA fragmentation. In the analyses using specific caspase-substrates, extremely high cleavage activity toward caspase-3/7/8 substrate was observed in HOEA-treated U937 cells, and weak activities of caspase-1 and -3 were detected. Analyses using specific caspase inhibitors suggested that caspase-3 and caspase-8 might be predominantly responsible for the cleavage activity. Activation of these caspases were also confirmed by western blotting in which significant levels of cleaved forms of caspase 3, caspase 8, and PARP were detected in HOEA-treated U937 cells. Our results suggest that HOEA is capable of inducing apoptosis in U937 cells in which caspase-3 and caspase-8 might play important roles. Since the cytotoxic effect of HOEA is not strictly specific to tumor cells, development of appropriate drug delivery system for selective tumor targeting is necessary for the clinical applications to reduce the possible side effects.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Leucemia/tratamento farmacológico , Rodófitas/química , Antineoplásicos/isolamento & purificação , Caspase 3/metabolismo , Caspase 8/metabolismo , Ácidos Graxos Insaturados/isolamento & purificação , Ácidos Graxos Insaturados/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Células U937
15.
BMC Cancer ; 21(1): 438, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33879127

RESUMO

BACKGROUND: Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of cell death, including apoptosis. Apoptosis is highly regulated programmed cell death that can be initiated mainly via two pathways, through death receptors (extrinsic) or involvement of the mitochondria (intrinsic). Induction of apoptosis via these pathways has been alluded following treatment with daunorubicin, but never compared in acute lymphoblastic leukaemia over a time course. METHODS: This study investigated the mechanisms of daunorubicin induced apoptosis in the treatment of CCRF-CEM, MOLT-4 (acute T-lymphoblastic leukaemia) and SUP-B15 (acute B-lymphoblastic leukaemia) cells. Cells were treated with daunorubicin for 4 h, and then placed in recovery medium (without daunorubicin) for 4 h, 12 h and 24 h. Apoptotic response was analysing using annexin-V expression, caspase activity, mitochondrial membrane potential change and an array to detect 43 apoptotic proteins. RESULTS: Daunorubicin induced apoptosis in all leukemic cell lines, but with different levels and duration of response. Both apoptosis levels and caspase activity increased after four hours recovery then declined in CCRF-CEM and MOLT-4 cells. However, SUP-B15 cells displayed initially comparable levels but remained elevated over the 24 h assessment period. Changes in mitochondrial membrane potential occurred in both MOLT-4 and CCRF-CEM cells but not in SUP-B15 cells. Expression of apoptotic proteins, including Bcl-2, Bax, caspase 3 and FADD, indicated that daunorubicin potentially induced both extrinsic and intrinsic apoptosis in both CCRF-CEM and MOLT-4 cells, but only extrinsic apoptosis in SUP-B15 cells. CONCLUSIONS: This study describes variations in sensitivities and timing of apoptotic responses in different leukaemia cell lines. These differences could be attributed to the lack of functional p53 in coordinating the cells response following cytotoxic treatment with daunorubicin, which appears to delay apoptosis and utilises alternative signalling mechanisms that need to be further explored.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Daunorrubicina/farmacologia , Anexina A5/genética , Anexina A5/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Daunorrubicina/uso terapêutico , Humanos , Leucemia/tratamento farmacológico , Leucemia/genética , Leucemia/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos
16.
Nat Commun ; 12(1): 1850, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767176

RESUMO

Artificial intelligence and machine learning (ML) promise to transform cancer therapies by accurately predicting the most appropriate therapies to treat individual patients. Here, we present an approach, named Drug Ranking Using ML (DRUML), which uses omics data to produce ordered lists of >400 drugs based on their anti-proliferative efficacy in cancer cells. To reduce noise and increase predictive robustness, instead of individual features, DRUML uses internally normalized distance metrics of drug response as features for ML model generation. DRUML is trained using in-house proteomics and phosphoproteomics data derived from 48 cell lines, and it is verified with data comprised of 53 cellular models from 12 independent laboratories. We show that DRUML predicts drug responses in independent verification datasets with low error (mean squared error < 0.1 and mean Spearman's rank 0.7). In addition, we demonstrate that DRUML predictions of cytarabine sensitivity in clinical leukemia samples are prognostic of patient survival (Log rank p < 0.005). Our results indicate that DRUML accurately ranks anti-cancer drugs by their efficacy across a wide range of pathologies.


Assuntos
Antineoplásicos/uso terapêutico , Biologia Computacional/métodos , Citarabina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Leucemia/tratamento farmacológico , Aprendizado de Máquina , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Leucemia/mortalidade , Neoplasias/tratamento farmacológico , Prognóstico , Proteômica/métodos
17.
Ciudad Autónoma de Buenos Aires; Comisión Nacional de Evaluación de Tecnologías de Salud; Marzo 2021. 30 p. (Informe de Evaluación de Tecnologías Sanitarias N°15, 15).
Monografia em Espanhol | LILACS, BINACIS, ARGMSAL | ID: biblio-1151674

RESUMO

El presente informe es producto del trabajo colaborativo de la Comisión Nacional de Evaluación de Tecnologías de Salud (CONETEC), dependiente del Ministerio de Salud de la Nación y creada por RM N° 623/2018. La CONETEC realiza evaluaciones y emite recomendaciones a la autoridad sanitaria sobre la incorporación, forma de uso, financiamiento y políticas de cobertura de las tecnologías sanitarias desde una perspectiva global del sistema de salud argentino. En sus evaluaciones y recomendaciones, la CONETEC tiene en cuenta criterios de calidad, seguridad, efectividad, eficiencia y equidad, evaluados bajo dimensiones éticas, médicas, económicas y sociales. Sus resultados son consensuados mediante discusiones públicas y ponderados a través de un marco de valor explícito, con la participación de todos los actores involucrados en el proceso de toma de decisiones en salud. Los informes y recomendaciones de esta comisión surgen de este proceso público, transparente y colaborativo, siendo de libre consulta y acceso para toda la sociedad.


Assuntos
Idoso , Leucemia/tratamento farmacológico , Leucemia/epidemiologia
18.
J Biochem Mol Toxicol ; 35(6): 1-10, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33724660

RESUMO

Among cancers, leukemia is a multistep progression that involves genetic modifications of normal hematopoietic progenitor cells to cancerous cells. In recent times, leukemia cases and their mortality rate have increased rapidly. Therefore, the immense need for a therapeutic approach is crucial that can control this type of cancer. Phyllanthin is a lignan compound constituent from the Phyllanthus species and has numerous beneficial effects as a dietary component. The present study aims to determine the impact of phyllanthin on the MOLT-4 cytotoxic effect. MOLT-4 cells and MS-5 cells were cultured at different concentrations of phyllanthin (5, 10, 25, 50, 75, and 100 µM/ml), and the viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The level of reactive oxygen species, the membrane potential of mitochondria, apoptosis by 2',7'-dichlorofluorescin-diacetate (DCF-DA), rhodamine, acridine orange (AO)/ethidium bromide (EB), 4',6-diamidino-2-phenylindole (DAPI)/propidium iodide (PI) staining, gene expression of signaling molecules, and protein levels were assessed by reverse-transcription polymerase chain reaction and western blot analysis. Phyllanthin did not show toxicity toward MS-5 cells and significantly decreased the cell viability of MOLT-4 cells with an IC50 value of 25 µM/ml. Also, phyllanthin induced the production of reactive oxygen species and led to the loss of mitochondrial membrane potential. AO/EB and DAPI/PI staining fluorescent image confirmed the induction of apoptosis by phyllanthin treatment. The messenger RNA (mRNA) expression of cell cycle regulator cyclin D1, antiapoptotic gene Bcl-2, NF-κB, and TNF-α decreased, but the proapoptotic Bax mRNA expression was increased. The phosphorylated protein levels of p-PI3K1/2, p-ERK1/2, and p-AKT were decreased, whereas the levels of p-p38 and p-JNKT1/2 increased. Our results confirmed that phyllanthin inhibits the MOLT-4 cells, increases apoptosis, and inhibits MOLT-4 migration and cell invasion. Therefore, phyllanthin can be used as a potential target for leukemia treatment.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Leucemia/metabolismo , Lignanas/farmacologia , MAP Quinase Quinase 4/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Leucemia/tratamento farmacológico , Leucemia/patologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-33740692

RESUMO

Methotrexate, as a folate antagonist, is one of the first anti-neoplasm drugs offered and is still used as an effective drug in the treatment of various malignancies. Methotrexate has a narrow treatment index and is associated with numerous side effects.In thisresearch, for the first time a double-solvent supramolecular system (DSS) was developed as an extractant without disperser solvent for dispersive liquid-liquid microextraction (DLLME). DSS - DLLME was applied to the extraction of methotrexate in plasma of children with acute leukemiaprior to itsdetermination by high-performance liquid chromatography-ultraviolet detection (HPLC - UV). In the present method, two long normal chain alcohols are mixed in a particular ratio, and then it is injected into the sample solution, which is on the magnetic stirrer. In this case, the mixture of the two alcohol changes to new supramolecular aggregate. This new supermolecule is used as an extractant, which has a higher extraction power than any of its components alone. Under the optimum conditions, the calibration graph was linear in the rage of 0.1-150 µg L-1 with detection limit of 0.03 µg L-1. Relative standard deviations (RSDs) including intra-day and inter-day of method based on7 replicate determinations of 100.0 µg L-1of methotrexate were 2.6% and 4.8%,respectively. The results proved that DSS - DLLME is a sensitive, very simple, inexpensive, environmental friendly, rapid and efficient method for the preconcentration of trace amount of drugs in biological samples.


Assuntos
Leucemia/tratamento farmacológico , Microextração em Fase Líquida/métodos , Metotrexato/sangue , Doença Aguda , Criança , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Limite de Detecção , Modelos Lineares , Metotrexato/isolamento & purificação , Metotrexato/uso terapêutico , Reprodutibilidade dos Testes , Solventes/química
20.
FASEB J ; 35(4): e21402, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33724567

RESUMO

Leukemias are challenging diseases to treat due, in part, to interactions between leukemia cells and the bone marrow microenvironment (BMME) that contribute significantly to disease progression. Studies have shown that leukemic cells secrete C-chemokine (C-C motif) ligand 3 (CCL3), to disrupt the BMME resulting in loss of hematopoiesis and support of leukemic cell survival and proliferation. In this study, a murine model of blast crisis chronic myelogenous leukemia (bcCML) that expresses the translocation products BCR/ABL and Nup98/HoxA9 was used to determine the role of CCL3 in BMME regulation. Leukemic cells derived from CCL3-/- mice were shown to minimally engraft in a normal BMME, thereby demonstrating that CCL3 signaling was necessary to recapitulate bcCML disease. Further analysis showed disruption in hematopoiesis within the BMME in the bcCML model. To rescue the altered BMME, therapeutic inhibition of CCL3 signaling was investigated using bone-targeted nanoparticles (NP) to deliver Maraviroc, an inhibitor of C-C chemokine receptor type 5 (CCR5), a CCL3 receptor. NP-mediated Maraviroc delivery partially restored the BMME, significantly reduced leukemic burden, and improved survival. Overall, our results demonstrate that inhibiting CCL3 via CCR5 antagonism is a potential therapeutic approach to restore normal hematopoiesis as well as reduce leukemic burden within the BMME.


Assuntos
Leucemia/tratamento farmacológico , Animais , Proteínas de Bactérias , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Proteínas de Fluorescência Verde , Leucemia/etiologia , Leucemia Mieloide Aguda , Proteínas Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Doses de Radiação
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