Abstract Bulbine natalensis and Chorophytum comosum are potential medicinal source for the treatment of cancers. Chronic myeloid leukaemia is a hematopoietic stem cells disorder treated by tyrosine kinase inhibitors but often cause recurrence of the leukaemia after cessation of therapy, hence require alternative treatment. This study determines the anti-cancer effect of leaf, root and bulb methanolic and aqueous extracts of B. natalensis and C. comosum in chronic human myelogenous leukaemia (K562) cell line by MTT, Hoechst bis-benzimide nuclear and annexin V stain assays. The root methanolic extract of B. natalensis and C. comosum showed a high cytotoxicity of 8.6% and 16.7% respectively on the K562 cell line at 1,000 μg/ml concentration. Morphological loss of cell membrane integrity causing degradation of the cell and fragmentation were observed in the root methanolic extract of both plants. A high apoptosis (p < 0.0001) was induced in the K562 cells by both leaf and root extracts of the C. comosum compared to the B. natalensis. This study shows both plants possess apoptotic effect against in vitro myelogenous leukaemia which contributes to the overall anti-cancer properties of B. natalensis and C. comosum to justify future therapeutic applications against chronic myelogenous leukaemia blood cancer.
Resumo Bulbine natalensis Baker e Chorophytum comosum (Thunb.) Jacques são potenciais fontes medicinais para o tratamento de cânceres. A Leucemia Mieloide Crônica (LMC) é um distúrbio das células-tronco hematopoiéticas que é tratado com inibidores da tirosina quinase, mas frequentemente, causa recorrência da leucemia após a interrupção da terapia, portanto, requer um tratamento alternativo. Este estudo determinou o efeito anticancerígeno de extratos metanólicos e aquosos de folha, raiz e bulbo de B. natalensis e C. comosum na linhagem celular de leucemia mieloide humana crônica (K562) por ensaios de MTT, Hoechst bis-benzimida nuclear e anexina V. O extrato metanólico da raiz de B. natalensis e C. comosum apresentou alta citotoxidade de 8,6% e 16,7% respectivamente, na linhagem celular K562 com a concentração de 1,000 μg / ml. Perda morfológica da integridade da membrana celular causando degradação dos núcleos, citoplasma e encolhimento celular foi observada no extrato metanólico da raiz de ambas as plantas. Uma alta apoptose (p <0,0001) foi induzida nas células K562 por extratos de folhas e raízes de C. comosum em comparação com B. natalensis. Este estudo mostrou que ambas as plantas possuem efeito apoptótico contra leucemia mieloide in vitro que contribui para as propriedades anticâncer gerais de B. natalensis e C. comosum para justificar futuras aplicações terapêuticas contra câncer de sangue de LMC.
Subject(s)Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Asphodelaceae , Apoptosis , K562 Cells
ABSTRACT Introduction: Treatment-free remission (TFR) is a new goal of chronic myeloid leukemia (CML) therapy. TFR is feasible when the patient has achieved a deep and stable molecular response and met the criteria required to ensure its success. Treatment discontinuation should not be proposed to the CML patient if minimum conditions are not met. In Brazil, for example, molecular tests (BCR::ABL1) are not broadly available, making it difficult to monitor the patients adequately. Objective: In this sense, providing TFR recommendations for Brazilian physicians are therefore necessary. These recommendations include the main criteria checklist to start the TKIs treatment discontinuing process in patients diagnosed with CML and the population-eligible characteristics for treatment discontinuation. Method: Age, risk score at diagnosis, TKI treatment duration, BCR::ABL1 transcripts type, depth of the molecular response for treatment discontinuation, treatment adherence, patient monitoring and withdrawal syndrome are essential factors to consider in TFR. After TKI discontinuation, BCR::ABL1 transcripts monitoring should be more frequent. When a major molecular response loss is observed during the monitoring of a patient in TFR, the TKI treatment should be resumed. Conclusion: These recommendations should serve as a basis for medical professionals interested in proposing TKI discontinuation for CML patients in clinical practice. It is important to highlight that, despite the benefits of TFR for the patients and the health system, it should only be feasible following the minimum standards proposed in this recommendation.
Subject(s)Humans , Adult , Middle Aged , Aged , Young Adult , Protein-Tyrosine Kinases , Leukemia, Myelogenous, Chronic, BCR-ABL Positive
La leucémie myéloïde chronique (LMC) est une hémopathie maligne caractérisée par la présence du chromosome Philadelphie ou du gène de fusion BCR/ABL1. Au Mali, les approches génétiques de diagnostic et d'évaluation de la réponse thérapeutique de la LMC font défaut d'où l'intérêt de développer la méthode FISH (Hybridation in situ en Fluorescence) pour diagnostiquer et évaluer la réponse thérapeutique de la LMC. Méthodes. Nous avons analysé les cellules sanguines de 25 patients référés pour diagnostic ou évaluation thérapeutique de la LMC. Nous avons réalisé la FISH sur des cellules interphasiques et des métaphases, et la capture d'images cellulaires a été faite avec un microscope à épifluorescence. Résultats. Au total, 25 patients ont été inclus dont 16 pour diagnostic et 9 pour évaluation thérapeutique. Nous avons obtenu un taux de succès de 92% pour l'obtention des métaphases. En outre, nous avons observé des réarrangements ABL1/BCR à la FISH chez 22 des 25 patients. Parmi ces 22 patients, 16 ont présenté un patron de signaux typiques et 6 des patrons de signaux atypiques. Conclusion. Nous avons établi la technique FISH au Mali pour le diagnostic et l'évaluation thérapeutique de la LMC et identifié des formes atypiques de la translocation t(9 ;22).
Objective. Chronic myeloid leukemia (CML) is a hematologic malignancy characterized by the presence of the Philadelphia chromosome or its molecular equivalent, the BCR/ABL1 fusion gene. Diagnosis and monitoring of CML are done by detecting this chromosome, the BCR/ABL1 gene, or the BCR/ABL1 transcript. In Mali, genetic tools of diagnosis and follow-up are still lacking, so we did this study with the objectives of developing the FISH technique to diagnose, to follow up, and to characterize the cytogenetic profile of CML patients. Methods. We carried out FISH technique by using the dual color dual fusion probe for BCR/ABL1 on interphase nuclei and metaphases. Slides were scanned with an epifluorescence microscope. Results. A total of 25 patients (16 for diagnostic and 9 for follow-up) were included. We achieved a 92% success rate for obtaining metaphases. The BCR/ABL1 gene fusion signal was present in 22 patients. Among those 22 patients, 16 presented a typical signal pattern and 6 presented atypical signal patterns. Conclusion. We set up the FISH technique in Mali for the diagnosis and the follow-up of CML patients and identified atypical translocation of t(9;22).
Subject(s)Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myeloid , Treatment Outcome , Outcome Assessment, Health Care , Diagnosis
Objective: To explore the impacts of socio-demographic and clinical co-variates on treatment responses and outcomes in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitor (TKI) and identified the predictive models for them. Methods: Data of newly diagnosed adult patients with CML-CP receiving first-line TKI and having complete socio-demographic data and clinical information were reviewed. Cox model was used to identify the independent variables associated with complete cytogenetic response (CCyR) , major molecular response (MMR) , molecular response 4 (MR(4)) and molecular response 4.5 (MR(4.5)) , as well as failure-free survival (FFS) , progression-free survival (PFS) , overall survival (OS) and CML-related OS. Results: A total of 1414 CML-CP patients treated with first-line imatinib (n=1176) , nilotinib (n=170) or dasatinib (n=68) were reviewed. Median age was 40 (18-83) years and 873 patients (61.7% ) were males. Result of the multivariate analysis showed that lower educational level (P<0.001-0.070) and EUTOS long-term survival intermediate or high-risk (P<0.001-0.009) were significantly associated with lower cumulative incidences of CCyR, MMR, MR(4) and MR(4.5), as well as the inferior FFS, PFS, OS and CML-related OS. In addition, those who were males, from rural households, had white blood cells (WBC) ≥120×10(9)/L, hemoglobin (HGB) <115 g/L and treated with first-line imatinib had significantly lower cumulative incidences of cytogenetic and/or molecular responses. Being single, divorced or widowed, having, rural household registration, WBC≥120×10(9)/L, HGB<15 g/L, and comorbidity (ies) was significantly associated with inferior FFS, PFS, OS, and/or CML-related OS. Thereafter, the patients were classified into several subgroups using the socio-demographic characteristics and clinical variables by cytogenetic and molecular responses, treatment failure and disease progression, as well as overall survival and CML-related OS, respectively. There were significant differences in treatment responses and outcomes among the subgroups (P<0.001) . Conclusion: Except for clinical co-variates, socio-demographic co-variates significantly correlated with TKI treatment responses and outcomes in CML-CP patients. Models established by the combination of independent socio-demographic and clinical co-variates could effectively predict the responses and outcome.
Subject(s)Adult , Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Demography , Humans , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Male , Protein Kinase Inhibitors/therapeutic use , Retrospective Studies , Treatment Outcome
OBJECTIVE@#To evaluate the efficacy of the second-line nilotinib and third-line dasatinib on chronic myelogenous leukemia (CML) with failed first- and second-line treatments, and analyze the influencing factors of the efficacy.@*METHODS@#Selected 83 patients in The Third People's Hospital of Kunshan City, Jiangsu Province with CML who were treated with nilotinib as the second-line treatment after the failure of the first-line treatment with imatinib as the second-line treatment group (referred to as the second-line group) from January 2014 to December 2018, and 61 CML patients who were treated by dasatinib as the third-line treatment group (referred to as the third-line group) after the failure of the second-line treatment with nilotinib; the first-line treatment with imatinib failed, but due to various reasons, the patients were fully after being informed of the possible serious consequences of not changing the drug treatment, 37 CML patients who were still required to continue imatinib treatment served as the control group. The hematological, genetic and molecular responses of each group were compared for 3, 6, and 24 months of treatment. LogistiC regression was used to analyze the factors affecting the second and third line curative effects.@*RESULTS@#The three groups had statistically significant differences in the rates of achieving CHR, MCyR, and MMR at 3, 6, and 12 months of treatment (P<0.05). Compared the two groups, the CHR rates of the second-line group at 3, 6, and 12 months of treatment were 100.00%, 97.59%, and 95.18%, respectively; higher than the third-line group's 90.16%, 86.89%, 83.61% and the control group's 83.78%, 75.68% and 72.97%; the CHR rate of the third-line group was higher than that of the control group at 6 and 12 months of treatment. The rates of reaching MCyR at 3, 6, and 12 months after treatment in the second-line group were 87.95%, 93.98% and 93.98%, respectively, while those in the third-line group were 80.33%, 88.52% and 86.89%, which were higher than those of the control group of 67.57%, 64.86% and 48.65%. The rates of achieving MMR at 3, 6, and 12 months of treatment in the second-line group were 19.28%, 33.72% and 60.24%, respectively, and those in the third-line group were 11.48%, 26.23% and 49.18%, which were higher than those of the control group of 0.00%, 2.70% and 0.00%; The rate of reaching MMR within 12 months of treatment in the second-line group was higher than that of the third-line group, and the differences was statistically significant (P<0.05). There was no significant difference in the rate of reaching MCyR between the second-line group and the third-line group at 3, 6, and 12 months, and the rate of reaching MMR at 3 and 6 months (P>0.05). The incidence of nausea and vomiting among the three main non-hematological adverse reactions, and the incidence of grade 1~2 anemia among the hematological adverse reactions were statistically significant (P<0.05). There was no significant difference in the incidence of rash, eyelid edema, diarrhea, thrombocytopenia, leukopenia and neutropenia in the three groups (P>0.05). The incidence of nausea and vomiting and grade 1~2 anemia in the second-line group and the third-line group were higher than that of the control group, and the difference was statistically significant (P<0.05). There were statistically significant differences in Sokal score, medication compliance, and hematological adverse reactions between the MMR group and the non-MMR group (P<0.05). Logistic regression analysis showed that dose reduction or withdrawal during the treatment period, and grade 3~4 hematological adverse reactions were the main factors affecting the second and third line curative effects (OR=22.160, 2.715, 95% CI=2.795-93.027, 1.882-48.834).@*CONCLUSION@#The second-line nilotinib and the third-line dasatinib have a better effect on CML patients who have failed the first and second-line treatments. Grade 3~4 hematological adverse reactions, dose reduction or withdrawal are risk factors that affect the efficacy of second and third-line treatments.
Subject(s)Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Treatment Outcome
OBJECTIVE@#To investigate the effects of dasatinib on the maturation of monocyte-derived dendritic cells (moDCs) derived from healthy donors (HDs) and chronic myelogenous leukemia (CML) patients.@*METHODS@#Peripheral blood mononuclear cells (PBMCs) were isolated from HDs (n=10) and CML patients (n=10) who had got the remission of MR4.5 with imatinib treatment. The generation of moDCs from PBMCs was completed after 7 days of incubation in DC I culture medium, and another 3 days of incubation in DC II culture medium with or without 25 nmol/L dasatinib. On the 10th day, cells were harvested and expression of molecules of maturation related marker were assessed by flow cytometry. The CD80+CD86+ cell population in total cells was gated as DCs in the fluorescence-activated cell storting (FACS) analyzing system, then the expression of CD83, CD40 or HLA-DR in this population was analyzed respectively.@*RESULTS@#The proportion of CD80+CD86+ cells in total cells didn't show a statistical difference between HD group and patient group (89.46%±9.70% vs 87.39%±9.34%, P=0.690). Dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.008) and HLA-DR (P=0.028) on moDCs derived from HDs compared with the control group, while the expression of CD83 on moDCs didn't show a significant difference between dasatinib group and the control group (P=0.428). Meanwhile, dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.023), CD83 (P=0.038) and HLA-DR (P=0.001) on moDCs derived from patients compared with the control group.@*CONCLUSION@#For CML patients, the same high proportion of moDCs as HDs can be induced in vitro, which provides a basis for the application of DC-based immunotherapy strategy. Dasatinib at the concentration of 25 nmol/L can efficiently promote the maturation of moDCs derived from HDs and CML patients in vitro. Dasatinib shows potential as a DC adjuvant to be applied in DC-based immunotherapy strategies, such as DC vaccine and DC cell-therapy.
Subject(s)Cell Differentiation , Cells, Cultured , Dasatinib/pharmacology , Dendritic Cells , HLA-DR Antigens/pharmacology , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukocytes, Mononuclear , Monocytes
Objetivo: Avaliar o impacto econômico da descontinuação do tratamento da leucemia mieloide crônica (LMC) com inibidores da tirosina quinase (ITQs) em primeira ou segunda linha. Métodos: O modelo incluiu pacientes com diagnóstico de LMC em tratamento com ITQs que iniciaram o tratamento até 2012, em condições elegíveis no ano de 2015. Foi considerado um horizonte temporal de cinco anos sob a perspectiva do sistema público de saúde. Custos associados ao tratamento, como medicamento, monitoramento e manejo de eventos adversos, foram analisados. A avaliação foi composta por dois cenários: o cenário referência, com uso contínuo do medicamento, e o cenário comparador, com a interrupção do tratamento medicamentoso. Ambos os cenários consideraram as tecnologias disponíveis no período de 2015 a 2019. A análise de sensibilidade propôs variações nos cenários com a finalidade de avaliar a robustez do modelo. Além disso, uma extrapolação para nível nacional foi realizada, utilizando dados epidemiológicos para a obtenção do número de pacientes. Resultados: Foram selecionados 268 pacientes que iniciaram o tratamento até 2012. Desses, 65 foram elegíveis à descontinuação. A análise econômica mostrou uma economia de R$ 670.558,10 no primeiro ano, uma economia acumulada em cinco anos de R$ 3.665.355,98 e de R$ 66.517.232,80 no contexto institucional e nacional, respectivamente. A análise de sensibilidade foi favorável em todos os cenários propostos. Conclusões: A descontinuidade do tratamento da LMC mostrou-se, economicamente, uma importante oportunidade sob a perspectiva do sistema de saúde em flexibilizar novos investimentos tecnológicos e/ou ampliação de cesso, além da melhoria na qualidade de vida do paciente.
Objective: To assess the economic impact of discontinuing treatment of chronic myeloid leukemia (CML) with first or second line tyrosine kinase inhibitors (ITQs). Methods: The model included patients diagnosed with CML undergoing treatment with ITQs who started treatment until 2012, under eligible conditions in the year 2015. A 5-year time horizon was considered from the perspective of the public health system. Costs associated with treatment, such as medication, monitoring and handling adverse events were analyzed. The evaluation consisted of two scenarios, the reference scenario with continuous use of the drug and the comparator scenario with the interruption of drug treatment. Both scenarios considered the technologies available in the period from 2015 to 2019. The sensitivity analysis proposed variations in the scenarios in order to assess the robustness of the model. In addition, an extrapolation to the national level was performed, using epidemiological data to obtain the number of patients. Results: 268 patients who started treatment until 2012 were selected. Of these, 65 were eligible for discontinuation. The economic analysis showed savings of R$ 670,558.10 in the first year, accumulated savings in five years of R$ 3,665,355.98 and R$ 66,517,232.80 in the institutional and national context, respectively. The sensitivity analysis was favorable in all the proposed scenarios. Conclusions: The discontinuity of CML treatment proved to be, economically, an important opportunity from the perspective of the health system in making new technological investments and / or expanding access more flexible, in addition to improving the patient's quality of life
Subject(s)Protein-Tyrosine Kinases , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Health Care Economics and Organizations
ABSTRACT This manuscript summarizes the results of the consensus meeting composed of hematologists and cardiologists to establish recommendations for the prevention and follow-up of cardiovascular (CV) risk in patients with chronic myeloid leukemia (CML) treated with BCR-ABL tyrosine kinase inhibitors (TKIs) from the point of view of clinical practice and from the perspective of hematology consultation.In the first medical appointment, the CV risk factors should be identified to perform the baseline risk stratification, based on the Brazilian Guideline of Dyslipidemia and Atherosclerosis Prevention Update (risk levels: very high, high, intermediate and low).Once stratified, the treatment of the CV risk factors should be administered. If the patient presents risk factors, such as hypertension, diabetes, renal disease, smoking and hypercholesterolemia, the evaluation and initial treatment may be done by the hematologist, being an option the request for evaluation by a specialist. If the patient has a history of previous CV disease, we recommend referral to a specialist. As the CV risk score is dynamic and the control of risk factors can reduce the patient risk, this expert consensus recommends that the re-evaluation of the CV risk after the baseline should be performed at 3 months, 6 months and 12 months. After this period, it should be done annually and, for specific patients, at the clinician's discretion.The evaluation of the baseline CV risk and the safe administration of a TKI allow the patient to benefit from the maximum treatment, avoiding unwanted effects.
Subject(s)Humans , Protein-Tyrosine Kinases , Cardiovascular Diseases/therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Heart Disease Risk Factors , Tobacco Use Disorder/prevention & control , Environmental Monitoring , Diabetes Mellitus/prevention & control , Hypertension/prevention & control
ABSTRACT Introduction: Chronic Myeloid Leukemia (CML) is a myeloproliferative disease that affects mainly adults between 50 and 55 years. In Brazil, information from the Sistema Único de Saúde (SUS) Outpatient Information System indicates that 12,531 patients had the Autorização de Procedimento Ambulatorial (APAC) approved for the CML treatment in 2017. Disease monitoring through molecular response evaluation is critical to the care of CML patients. The quantitative PCR test (real-time polymerase chain reaction) provides adequate evaluation parameters that allow the health professional to intervene at the right moments in order to reduce the chance of progression of the disease, providing the best outcome to the patient, including the possibility of treatment discontinuation for eligible patients. Although the test is included in the Clinical Protocol and Therapeutic Guidelines (PCDT) of CML, it is not possible to monitor the molecular response within SUS since there is no reimbursement for this test. Objective: Obtain expert recommendations on the importance, financing, and reimbursement of molecular monitoring in SUS. Methods: Six CML experts with different perspectives participated in the panel. The discussion was based in the main publications about the quantitative PCR test in CML monitoring. Results: Experts' recommendations: Molecular monitoring should be part of the integral treatment of patients with CML to reduce the chances of disease progression and costs to the health system; The government should put into practice what is provided in the PCDT of Chronic Myeloid Leukemia in Brazil: performing the monitoring of the molecular response via quantitative PCR; The government should create a code with adequate nomenclature and reimbursement value in SIGTAP, so that the test is carried out and covered by the public health network, as it is contained in the PCDT of the disease and the existing APAC does not cover the operational costs for its performance; Patients with chronic phase CML should perform a quantitative PCR every 3 months and, after reaching the MMR, should perform the examination every 6 months, as recommended by international guidelines; Patients should be monitored in reference laboratories that are standardized according to the international scale; The laboratories that are within the reference public centers could absorb all the test demand in Brazil, and other centers could be qualified through an ABHH accreditation; Adequate molecular monitoring may allow some patients to stop taking drugs and selffinancing the molecular test for all SUS patients Conclusion: A solution for the molecular test (BCR-ABL1) funding is urgent to ensure the monitoring of CML patients in SUS. The savings that might be generated with patients that stop taking the medication when adequately monitored may finance the test.
Subject(s)Humans , Middle Aged , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Real-Time Polymerase Chain Reaction , Reimbursement Mechanisms , Unified Health System , Brazil , Genes, abl
Descrição: Relato de caso de um paciente com um transcrito raro (e1a2) na Leucemia Mieloide Crônica (LMC) e outro com uma translocação rara na Síndrome Mielodisplásica (SMD). Discussão: O transcrito e1a2 possui frequência de 1% entre os casos de LMC, já a translocação t(11,17)(q23;q21) não foi evidenciada em paciente com SMD do tipo Anemia Refratária com Excesso de Blastos (AREB) do tipo 2. Conclusão: Ambos os casos apresentados possuem associação incomum entre fenótipo e genótipo. A correlação da clínica com os achados laboratoriais é importante para a determinação fidedigna do diagnóstico e prognóstico destes pacientes.
Description: Case report of a patient with a rare transcript (e1a2) in Chronic Myeloid Leukemia (CML) and another with a rare translocation in Myelodysplastic Syndrome (SMD). Discussion: The transcript e1a2 has a frequency of 1% in CML cases, whereas t (11,17) (q23; q21) translocation was not observed in a patient with type of Refractory Anemia with Excess Blasts (AREB) type 2. Conclusion: Both cases reported have unusual association between phenotype and genotype. The correlation of the clinic with the laboratory findings is important for the reliable determination of the diagnosis and prognosis of these patients.
Subject(s)Humans , Female , Middle Aged , Phenotype , Translocation, Genetic , Anemia, Refractory , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia , Hematologic Neoplasms , Genotype
Myeloid sarcoma (MS) is a rare extramedullary neoplasm of myeloid cells, which can arise before, concurrently with, or following hematolymphoid malignancies. We report 04 such cases of MS, diagnosed in this institute over a period of 6 years, during various phases of their respective myeloid neoplasms/leukemias. These cases include MS occurring as a relapse of AML (Case 1), MS occurring as an initial presentation of CML (Case 2), MS occurring during ongoing chemotherapy in APML (Case 3), and MS presenting as a progression of MDS to AML (Case 4). In the absence of relevant clinical history and unemployment of appropriate immunohistochemical (IHC) studies, these cases have a high risk of being frequently misdiagnosed either as Non-Hodgkin's Lymphoma (NHL) or small round cell tumors or undifferentiated carcinomas, which may further delay their management, making an already bad prognosis worse. This case series has been designed to throw light on the varied presentation of MS and the lineage differentiation of its neoplastic cells through the application of relevant IHC markers along with their clinical correlation.
Subject(s)Humans , Male , Female , Child, Preschool , Adolescent , Middle Aged , Aged , Sarcoma, Myeloid/pathology , Myelodysplastic Syndromes/pathology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemia, Myeloid, Acute/pathology , Leukemia, Promyelocytic, Acute/pathology , Diagnostic Errors/prevention & control
Tanshinone I (Tan I) is one of the main bioactive ingredients derived from Salvia miltiorrhiza Bunge, which has exhibited antitumor activities toward various human cancer cells. However, its effects and underlying mechanisms on human chronic myeloid leukemia (CML) cells still require further investigation. This study determined the effects and mechanisms of anti-proliferative and apoptosis induction activity induced by Tan I against K562 cells. The cytotoxic effect of Tan I at varying concentrations on K562 cells was evaluated via MTT assay. Cell apoptosis was further investigated through DAPI staining and flow cytometry analysis. The expression levels of apoptosis-related proteins and activities of JNK/ATF2 and ERK signaling pathways were analyzed by western blot. Quantitative PCR was performed to further determine mRNA expression levels of JNK1/2 and ERK1/2 after Tan I treatment. The results indicated that Tan I significantly inhibited K562 cell growth and induced apoptosis in a concentration- and time-dependent manner. It induced significant cellular morphological changes and increased apoptosis rates in CML cells. Tan I promoted the cleavages of caspase-related proteins, as well as increased the expression levels of PUMA. Furthermore, Tan I significantly activated JNK and inhibited ATF-2 and ERK signaling pathways. The mRNA expression levels of JNK1/2 and ERK1/2 were up-regulated by Tan I, further confirming its regulatory effects on JNK/ERK signaling pathways. Overall, our results indicated that Tan I suppressed cell viability via JNK- and ERK-mediated apoptotic pathways in K562 cells, suggesting that it might be a promising candidate as a novel anti-leukemia drug.
Subject(s)Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Abietanes/pharmacology , Apoptosis , Cell Line, Tumor
The seed oil of Annona salzmannii A. DC. was analyzed by GC-MS and 1H qNMR, revealing a mixture of unsaturated (80.5%) and saturated (18.7%) fatty acids. Linoleic (45.3%) and oleic (33.5%) acid were the major unsaturated fatty acids identified, while palmitic acid (14.3%) was the major saturated fatty acid. The larvicidal effects of A. salzmannii seed oil were evaluated against third-instar larvae of Aedes aegypti (Linn.). The oil exhibited moderate larvicidal activity, with a LC50 of 569.77 ppm (95% CI = 408.11 to 825.88 ppm). However, when the cytotoxic effects of the oil were evaluated, no expressive antiproliferative effects were observed in tumor cell lines B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), K562 (human chronic myelocytic leukemia), HL-60 (human promyelocytic leukemia), and non-tumor cell line PBMC (peripheral blood mononuclear cells), with IC50 values > 50 µg·mL-1. This is the first study to evaluate the chemical composition, larvicidal and cytotoxic activity of A. salzmannii seed oil
Subject(s)Seeds/anatomy & histology , Plant Oils/analysis , Annonaceae/chemistry , Annona/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Fatty Acids, Unsaturated , Larva/classification
OBJECTIVE@#To explore the expression level of ETV6-ABL fusion gene in different cell populations in patients with myeloproliferative neoplasm (MPN) and therapeutic effect of tyrosine kinase inhibitor (TKI).@*METHODS@#A 42-year-old man who presented with fever, marked leukocytosis and chronic myelogenous leukemia (CML) like MPN was reported. ETV6-ABL fusion gene was detected by real-time PCR and confirmed by direct sequencing. ETV6-ABL mRNA expression in each cell population sorted from peripheral blood by flow cytometry was detected by real-time PCR.@*RESULTS@#ETV6-ABL fusion gene was found out in bone marrow cells and confirmed as type A by direct sequencing. ETV6-ABL fusion gene transcript level in polymorphonuclear cells was nearly 3.6-fold relative to that in total cells, which was significantly higher than that in T cell, B cell and monocyte subsets. The complete blood count (CBC) returned to normal level after treatment with imatinib (400 mg) daily for three months. After TKI treatment for 6 months, the ratio of ETV6-ABL/ABL decreased from 174.1% to 1.9%.@*CONCLUSION@#ETV6-ABL fusion gene positive MPN may have a CML clinical presentation and is sensitive to TKI. ETV6-ABL fusion gene is specifically expressed in polymorphonuclear cells.
Subject(s)Adult , Fusion Proteins, bcr-abl/genetics , Genes, abl , Hematopoietic Stem Cell Transplantation , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Myeloproliferative Disorders/genetics
Chronic myeloid leukemia with a significant increase of monocytes is rare and difficult to identify from chronic myelo-monocytic leukemia in clinic. A 31-year-old male patient with systemic pain was initially diagnosed as chronic myelo-monocytic leukemia, who was finally diagnosed as chronic myeloid leukemia by fusion gene and chromosome examination. In addition to the typical Ph chromosome, a rare chromosome translocation t(2; 7)(p13; p22) was observed. The detection of monocyte subsets by multi-parameter flow cytometry is a diagnostic marker to distinguish the above 2 diseases. The relationship between fusion genes and mononucleosis is not clear. Tyrosine kinase inhibitors or allogeneic hematopoietic stem cell transplantation can be used in the treatment for this disease.
Subject(s)Adult , Humans , Karyotype , Karyotyping , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Monocytes , Translocation, Genetic
OBJECTIVE@#To evaluate the clinical efficacy and safety of domestic imatinib (made in China) in patients with newly diagnosed chronic myeloid leukemia chronic phase(CML-CP).@*METHODS@#Fifty-seven newly diagnosed CML-CP patients who did not receive any other anti-CML treatment were treated by domestic imatinib 400 mg once a day. The hematological, cytogenetic and molecular reactions and safety were observed and evaluated after 3, 6 and 12 months of treatment.@*RESULTS@#Fifty-six patients were treated for ≥3 and 6 months, among which 50 patients were treated for ≥12 months. After 3 months of treatment, 49 patients underwent hematological examination, 47 patients (95.9%) achieved complete hematological response (CHR), 49 patients underwent cytogenetic examination, 39 patients (79.6%) achieved major cytogenetic response (MCyR), and 12 patients (24.5%) achieved complete cytogenetic response (CCyR). 49 patients underwent the level of BCR-ABL test, including 41 patients (83.7%) with BCR-ABL@*CONCLUSION@#In the real world, Domestics imatinib mesylate is effective and safe in the treatment of newly diagnosed CML-CP patients, but long-term follow-up data are still necessary to verify its long-term efficacy.
Subject(s)Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , China , Fusion Proteins, bcr-abl/genetics , Humans , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines , Pyrimidines/therapeutic use , Treatment Outcome
OBJECTIVE@#To investigate the effect of etoposide (ETO) on elimination of chronic myeloid leukemia (CML) stem cells by imatinib mesylate(IM) in vivo.@*METHODS@#SCL-tTA/BCR-ABL mice were used as CML animal model. Flow cytometry was used to assess the effect of ETO alone or in combination with IM on the number of leukemia stem cell （LSC） in bone marrow and spleen, and peripheral blood neutrophils in CML mice and normal control FVB mice.@*RESULTS@#The results showed that in CML mice, the number and proportion of LSC in bone marrow and the proportion of neutrophils in peripheral blood decreased significantly after ETO and IM combined treatment, and the degree of decrease was more significant than that of both alone. While in wild type FVB mice, the combination of ETO and IM showed no significant effect on the number and proportion of LSK cells in bone marrow and the proportion of neutrophils in spleen.@*CONCLUSION@#ETO can selectively enhance elimination of CML LSC by IM in vivo.
Subject(s)Animals , Drug Resistance, Neoplasm , Etoposide , Fusion Proteins, bcr-abl , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mice , Stem Cells
OBJECTIVE@#The present study was to evaluate the anti-tumor effects of acidic RNA protein complex (FA-2-b-β) extracted from the wild edible Qinba mushroom in inducing of apoptosis and immunoregulation of tumor cell.@*METHODS@#Cell proliferation inducing rate of FA-2-b-β to K562 cell was measured using CCK-8. Apoptosis rate was detected by using flow cytometry. Chronic myeloid leukemia model was developed by tail vein injection/subcutaneous inoculation of K562 cells in NCG mice. The tumor burden of mice was observed. The general condition of the mice was monitored twice daily. The peripherivcal full blood counts of mice was tested daily. RT-qPCR and Western blot was FA-2-b-β performed to determine involvement of apoptotic-related gene and protenin, Immunofluorescence and immunohistochemistry was used to detected the expression of CD3, CD4 and CD8.@*RESULTS@#The proliferation and apoptosis of K562 cell could be inhibitied and induced by FA-2-b-β, there was 100% successful in the tumor formation in vivo, after treated by drug for 21 days there were significantly increased peripheral leucocytes, but decreased hemoglobin of mice treated by FA-2-b-β as compared with those in control group. The CD3, CD4 and CD8 showed positive in mice, and the propotation was imbalance, but it showed reserved after treated by FA-2-b-β.@*CONCLUSION@#FA-2-b-β is strong anti-leukemia effect in vitro and in vivo, suggesting the traditional Chinese medicine maybe contribute to the anti-cancer and immunoregulation research.