RESUMEN
Tyrosine kinase inhibitors (TKIs) offer targeted therapy for cancers but can cause severe cardiotoxicities. Determining their dosedependent impact on cardiac function is required to optimize therapy and minimize adverse effects. The dosedependent cardiotoxic effects of two TKIs, imatinib and ponatinib, were assessed in vitro using H9c2 cardiomyoblasts and in vivo using zebrafish embryos. In vitro, H9c2 cardiomyocyte viability, apoptosis, size, and surface area were evaluated to assess the impact on cellular health. In vivo, zebrafish embryos were analyzed for heart rate, blood flow velocity, and morphological malformations to determine functional and structural changes. Additionally, reverse transcriptionquantitative PCR (RTqPCR) was employed to measure the gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), established markers of cardiac injury. This comprehensive approach, utilizing both in vitro and in vivo models alongside functional and molecular analyses, provides a robust assessment of the potential cardiotoxic effects. TKI exposure decreased viability and surface area in H9c2 cells in a dosedependent manner. Similarly, zebrafish embryos exposed to TKIs exhibited dosedependent heart malformation. Both TKIs upregulated ANP and BNP expression, indicating heart injury. The present study demonstrated dosedependent cardiotoxic effects of imatinib and ponatinib in H9c2 cells and zebrafish models. These findings emphasize the importance of tailoring TKI dosage to minimize cardiac risks while maintaining therapeutic efficacy. Future research should explore the underlying mechanisms and potential mitigation strategies of TKIinduced cardiotoxicities.
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Cardiotoxicidad , Mesilato de Imatinib , Imidazoles , Miocitos Cardíacos , Piridazinas , Pez Cebra , Animales , Pez Cebra/embriología , Imidazoles/toxicidad , Piridazinas/efectos adversos , Piridazinas/farmacología , Piridazinas/toxicidad , Mesilato de Imatinib/toxicidad , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/farmacología , Cardiotoxicidad/etiología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/toxicidad , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular , Péptido Natriurético Encefálico/metabolismo , Péptido Natriurético Encefálico/genética , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Mioblastos Cardíacos/efectos de los fármacos , Mioblastos Cardíacos/metabolismo , RatasRESUMEN
BACKGROUND: To evaluate the outcomes of first-line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML-CP) in real-world clinical practice. METHODS: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. RESULTS: Nilotinib-treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib-treated patients. However, there was no significant difference in 5-year overall survival (OS) or progression-free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib-treated patients had a higher failure-free survival (FFS) and event-free survival (EFS) than imatinib-treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). CONCLUSIONS: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.
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Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Pirimidinas , Humanos , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Adulto , Anciano , Resultado del Tratamiento , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Puntaje de Propensión , Supervivencia sin Progresión , Adulto JovenRESUMEN
BACKGROUND: In Nigeria, since 2002, Imatinib mesylate (glivec®) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria. METHOD: This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002-2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1-1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant. RESULTS: The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal (r = 0.733, p = 0.011) and EUTOS (r = 0.102, p = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively. CONCLUSION: This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria.
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Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Mesilato de Imatinib/uso terapéutico , Nigeria , Pronóstico , Resultado del Tratamiento , Anciano , Adulto Joven , Antineoplásicos/uso terapéutico , Adolescente , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , PobrezaRESUMEN
BACKGROUND: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the BCR::ABL1 fusion gene arising from the Philadelphia chromosome (Ph) translocation t(9:22)(q34;q11), exhibits diverse clinical courses often influenced by additional chromosomal aberrations (ACAs). This report presents a case of CML har-boring a novel four-way Ph translocation involving the X chromosome, offering insights into the interplay between complex karyotypes and treatment response and emphasizing the need for further research into the role of ACAs in CML management. METHODS: A 42-year-old man diagnosed with CML in the accelerated phase presented a novel four-way Ph translocation involving chromosomes X, 5, 9, and 22: 46,Y,t(X;5;9;22)(q26;q15;q34;q11.2). Despite achieving a major molecular response initially with imatinib and nilotinib, BCR::ABL1 levels (international scale) increased up to 24.0%, which prompted the use of second-line nilotinib. RESULTS: Follow-up bone marrow (BM) studies revealed clonal evolution with trisomy 8 and an unclassified ABL1 mutation (E292V), potentially contributing to resistance. Though a transient major molecular response (MMR) occurred after a switch to third-line dasatinib, this change failed to achieve a deep molecular response, and BCR-ABL1 levels were elevated above the MMR. CONCLUSIONS: This case highlights the challenge of ACAs impacting CML treatment response and prognosis. Limited knowledge exists on complex Ph translocations involving the X chromosome, but this report contributes data for further research. Understanding ACA effects on therapeutic response and prognosis requires a detailed study of such complex chromosomal aberrations.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Cromosoma Filadelfia , Translocación Genética , Humanos , Masculino , Adulto , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Evolución Clonal/genética , Proteínas de Fusión bcr-abl/genética , Mesilato de Imatinib/uso terapéutico , Pirimidinas/uso terapéutico , Cromosomas Humanos X/genética , Antineoplásicos/uso terapéuticoAsunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/historia , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Historia del Siglo XX , Historia del Siglo XXI , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/historia , /efectos adversos , Ensayos Clínicos Fase III como Asunto , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the anti- chronic myelogenous leukemia (CML) activity of Nur77-specific agonist Csn-B combined with imatinib by promoting Nur77 expression, and explore the potential role of its signaling pathway. METHODS: Firstly, CCK-8 and Transwell assay were used to detect the inhibitory effects of Csn-B, imatinib, and their combination on the proliferation and migration of K562 cells. Furthermore, the apoptosis rate of K562 cells treated with Csn-B, imatinib, and their combination was detected by flow cytometry. The expression levels of Nur77, Pim-1, Drp1, p-Drp1 S616, Bcl-2 and Bax in K562 cells were detected by Western blot. Finally, the expression levels of reactive oxygen species (ROS) in K562 cells treated with Csn-B, imatinib and their combination were detected by immunofluorescence assay. RESULTS: The level of Nur77 in CML patients decreased significantly compared with normal population in dataset of GSE43754 (P < 0.001). Csn-B combined with imatinib could significantly inhibit the proliferation and migration of K562 cells (both P < 0.001), and induce apoptosis (P < 0.001). Csn-B promoted Nur77 expression in K562 cells, and synergistically enhanced imatinib sensitivity when combined with imatinib. Csn-B combined with imatinib could significantly enhanced ROS levels in K562 cells and mitochondria compared with single-drug treatment (both P < 0.001). CONCLUSION: Csn-B combined with imatinib can enhance ROS expression and induce apoptosis of K562 cells through Nur77/Pim-1/Drp1 pathway.
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Apoptosis , Proliferación Celular , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Proteínas Proto-Oncogénicas c-pim-1 , Humanos , Mesilato de Imatinib/farmacología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Células K562 , Proliferación Celular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Dinaminas , Transducción de Señal , Especies Reactivas de Oxígeno/metabolismo , Movimiento CelularAsunto(s)
Antineoplásicos , Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Humanos , Mesilato de Imatinib/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patologíaRESUMEN
Imatinib-induced skin rash poses a significant challenge for patients with gastrointestinal stromal tumor, often resulting in treatment interruption or discontinuation and subsequent treatment failure. However, the underlying mechanism of imatinib-induced skin rashes in gastrointestinal stromal tumor patients remains unclear. A total of 51 patients (27 with rash and 24 without rash) were enrolled in our study. Blood samples were collected concomitantly with the onset of clinical manifestations of rashes, and simultaneously collecting clinical relevant information. The imatinib concentration and untargeted metabolomics were performed by ultra-high-performance liquid chromatography-tandem mass spectrometry. There were no significant differences in age, gender, imatinib concentration and white blood cells count between the rash group and the control group. However, the rash group exhibited a higher eosinophil count (P<0.05) and lower lymphocyte count (P<0.05) compared to the control group. Untargeted metabolomics analysis found that 105 metabolites were significantly differentially abundant. The univariate analysis highlighted erucamide, linoleoylcarnitine, and valine betaine as potential predictive markers (AUC≥0.80). Further enriched pathway analysis revealed primary metabolic pathways, including sphingolipid signaling pathway, sphingolipid metabolism, cysteine and methionine metabolism, biosynthesis of unsaturated fatty acids, arginine and proline metabolism, and biosynthesis of amino acids. These findings suggest that the selected differential metabolites could serve as a foundation for the prediction and management of imatinib-induced skin rash in gastrointestinal stromal tumor patients.
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Antineoplásicos , Exantema , Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Metabolómica , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Exantema/inducido químicamente , Neoplasias Gastrointestinales/tratamiento farmacológico , Anciano , AdultoRESUMEN
Recent studies have emphasized the critical role of alteration in cellular plasticity in the development of fibrotic disorders, particularly pulmonary fibrosis, prompting further investigation into molecular mechanisms and therapeutic approaches. In this context, Precision Cut Lung Slices (PCLSs) emerge as a valuable ex vivo research tool. The process of PCLSs generation preserves most features of the naïve lung tissue, such as its architecture and complex cellular composition. We previously stimulated normal lung PCLSs with two different stimuli (fibrotic cocktail, composed by platelet lysate and TGFß, or neutrophil extracellular traps) and we observed a significant elevation of Epithelial-Mesenchymal Transition (EMT) markers from 24 h to 72 h of culture. The aim of our work was to exploit this PCLSs based ex vivo model of EMT, to evaluate the effect of imatinib, an old tyrosine kinase inhibitor with reported anti-remodeling activities in vitro and in animal models. Imatinib treatment significantly decreased α-SMA and collagen expression already starting from 24 h on stimulated PCLS. Imatinib showed a significant toxicity on unstimulated cells (3-fold increase in ACTA2 expression levels at 24 h, 1.5-fold increase in COL1A1 expression levels at 24 h, 2-fold increase in COL3A1 expression levels at 72 h). Further evaluations on specific cell lines pointed out that drug effects were mainly directed towards A549 and LFs. In conclusion, our model confirms the anti-remodeling activity of imatinib but suggests that its direct delivery to alveolar epithelial cells as recently attempted by inhalatory preparation of the drug might be associated with a non-negligible epithelial cell toxicity.
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Transición Epitelial-Mesenquimal , Mesilato de Imatinib , Pulmón , Mesilato de Imatinib/farmacología , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Células A549 , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Inhibidores de Proteínas Quinasas/farmacología , Actinas/metabolismoRESUMEN
BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
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Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Inhibidores de Proteínas Quinasas , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/mortalidad , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Francia , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/mortalidad , Supervivencia sin Progresión , Adulto , Factores de Tiempo , Resistencia a Antineoplásicos , Privación de Tratamiento/estadística & datos numéricos , Esquema de MedicaciónRESUMEN
Understanding the determinants of long-term liver metastasis (LM) outcomes in gastrointestinal stromal tumor (GIST) patients is crucial. We established the feature selection model of intratumoral microbiome at the surgery, achieving robust predictive accuracies of 0.953 and 0.897 AUCs in discovery (n = 74) and validation (n = 34) cohorts, respectively. Notably, despite the significant reduction in LM occurrence with adjuvant imatinib (AI) treatment, intratumoral microbiome exerted independently stronger effects on post-operative LM. Employing both 16S and full-length rRNA sequencing, we pinpoint intracellular Shewanella algae as a foremost LM risk factor in both AI- and non-AI-treated patients. Experimental validation confirmed S. algae's intratumoral presence in GIST, along with migration/invasion-promoting effects on GIST cells. Furthermore, S. algae promoted LM and impeded AI treatment in metastatic mouse models. Our findings advocate for incorporating intratumoral microbiome evaluation at surgery, and propose S. algae as a therapeutic target for LM suppression in GIST.
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Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Neoplasias Hepáticas , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/microbiología , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/microbiología , Animales , Ratones , Femenino , Masculino , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/microbiología , Quimioterapia Adyuvante/métodos , Persona de Mediana Edad , Microbiota/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , AncianoRESUMEN
OBJECTIVE: A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial ß-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells. METHODS: HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer. RESULTS: This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model. CONCLUSIONS: This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.
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Carnitina , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Miembro 5 de la Familia 22 de Transportadores de Solutos , Carnitina/metabolismo , Carnitina/farmacología , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/efectos adversos , Animales , Humanos , Ratones , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Miembro 5 de la Familia 22 de Transportadores de Solutos/metabolismo , Línea Celular Tumoral , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Metabolismo Energético/efectos de los fármacos , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/efectos adversos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacosRESUMEN
BCR-ABL1-independent resistance to imatinib has no effective treatment due to its complexity and diversity. We previously reported that the CDH13 oncogene was expressed at low levels in BCR-ABL1-independent resistant CML cell lines. However, its effects on CML resistant cells and mechanisms remain unknown. This study investigated the effects of saRNA-based CDH13 activation on BCR-ABL1-independent imatinib resistance in CML and its underlying mechanism, and proposes a unique treatment method to overcome imatinib resistance. Specifically, this study demonstrated that using the DSIR (Designer of Small Interfering RNA) website tool, saRNAs targeting the CDH13 promoter region were generated and validated using qPCR and western blotting. Among the predicted sequences, C2 and C3 efficiently elevated CDH13 mRNA and protein expression, as well as inhibited the relative vitality of cells and the ability to form clones. After promoting CDH13 expression in K562-IMR cells, it inhabited the NF-κB signaling pathway and induced apoptosis in imatinib-resistant CML cells. LNP-saRNA (C3) was also observed to limit the growth of K562-IMR cells in vivo. From the above, the activation of CDH13 expression by saRNA promotes cell apoptosis by inhibiting the NF-κB signaling pathway to overcome to BCR-ABL1-independent resistance to imatinib in patients with CML.
Asunto(s)
Cadherinas , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Transducción de Señal , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Cadherinas/metabolismo , Cadherinas/genética , Transducción de Señal/efectos de los fármacos , Proteínas de Fusión bcr-abl/metabolismo , Proteínas de Fusión bcr-abl/genética , Células K562 , ARN Interferente Pequeño/metabolismo , Animales , Apoptosis/efectos de los fármacos , Ratones , FN-kappa B/metabolismo , Ratones Desnudos , Línea Celular TumoralRESUMEN
BACKGROUND Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, which results from the fusion of the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, forming the BCR-ABL gene on chromosome number 22, which accounts for approximately 95% of CML cases. Complex translocation involving other chromosomes can occur. CASE REPORT We present a rare case of CML with a variant Ph chromosome, in which chromosome 16 was involved with the usual translocation. A 34-year-old woman presented with a history of left upper quadrant pain and excessive sweating, with no hepatosplenomegaly on examination. She was found to have leukocytosis, with elevated neutrophils (34 000/mm³), basophils (1460/mm³), and eosinophils (2650/mm³). Karyotyping showed a translocation (16;22) (q24,q11.2), and FISH analysis showed BCR-ABL fusion as a result of (9,22) translocation, with a third chromosome (chromosome 16) involved and fused with chromosome 22, with a different breakpoint, which has never been reported in the literature, affecting the long arm of chromosome 16. The patient was treated with a first-generation tyrosine kinase inhibitor (imatinib) and achieved a deep molecular remission. The repeated FISH analysis confirmed the disappearance of both translocations (9,22) and (16,22). CONCLUSIONS The impact of the additional chromosomal aberration in CML is widely heterogeneous, and the outcome is dependent on multiple factors. Larger studies are needed to clarify the outcome in CML with variant Ph chromosomes, as most of the available data come from reported cases.
Asunto(s)
Cromosomas Humanos Par 16 , Leucemia Mielógena Crónica BCR-ABL Positiva , Cromosoma Filadelfia , Translocación Genética , Humanos , Femenino , Adulto , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Cromosomas Humanos Par 16/genética , Mesilato de Imatinib/uso terapéutico , Proteínas de Fusión bcr-abl/genéticaRESUMEN
Chronic myelogenous leukemia (CML) is a hematological malignancy originating from the pluripotent hematopoietic stem cells. Imatinib is the first generation of small molecule tyrosine kinase inhibitors (TKI) that revolutionized the treatment of CML. Flumatinib, as a novel oral TKI that independently developed in China, which can be used as a preferred treatment for CML. Basic researches suggested that the inhibitory effect of flumatinib on CML cell lines is stronger than imatinib. Flumatinib demonstrated that it has better efficacy than imatinib on CML in clinical trials and in real world studies. Flumatinib also showed a higher potency against CML with specific mutations, Ph(+) acute lymphoblastic leukemia and some solid tumors. The adverse events are manageable and tolerable.
Asunto(s)
Aminopiridinas , Benzamidas , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Benzamidas/farmacología , Aminopiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piperazinas/farmacología , Mesilato de Imatinib/farmacología , Pirimidinas/farmacología , Antineoplásicos/farmacologíaRESUMEN
Imatinib, a small molecule kinase inhibitor, is used as a cancer growth blocker. However, one of its most serious side effects is congestive cardiac failure. Reducing drug toxicity may be achieved through the use of drug delivery systems. Biocompatible metal-organic framework (MOF) materials, namely FeMIL-100 and FeMIL-101-NH2, were employed as potential imatinib carriers. They efficiently delivered the drug as an anticancer agent while minimizing cardiotoxicity. Notably, the release of imatinib from FeMIL-100 was rapid in acidic conditions and slower in pH-neutral environments, allowing targeted delivery to cancer cells. The carrier's pH-dependent stability governed the drug release mechanism. Two release models-Korsmeyer-Peppas and Weibull-were fitted to the experimental data and discussed in terms of drug release from a rigid microporous matrix. Cytotoxicity tests were conducted on two cell lines: HL60 (a model cell line for acute myeloid leukemia) and H9c2 (a cell line for cardiomyocytes). Overall, the metal-organic framework (MOF) carriers mitigated imatinib's adverse effects without compromising its effectiveness.
Asunto(s)
Antineoplásicos , Portadores de Fármacos , Mesilato de Imatinib , Estructuras Metalorgánicas , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/química , Humanos , Estructuras Metalorgánicas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Portadores de Fármacos/química , Cardiotoxicidad/prevención & control , Liberación de Fármacos , Supervivencia Celular/efectos de los fármacos , Células HL-60 , Concentración de Iones de Hidrógeno , AnimalesRESUMEN
BACKGROUND/AIM: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses and a multifactorial etiology. While imatinib has demonstrated efficacy in the treatment of immune-related diseases, its potential effects in IBD treatment remain underexplored. MATERIALS AND METHODS: This study aimed to investigate the therapeutic effects of imatinib in colitis treatment. A dextran sulfate sodium (DSS)-induced colitis model was used to mimic IBD in mice. Imatinib was administered orally to mice simultaneously with DSS treatment. The effects of imatinib on DSS-induced colitis were evaluated by analyzing colitis-related pathology, including the disease activity index (DAI), histological lesions, inflammatory markers, and tight junction integrity. Additionally, western blot analysis and quantitative real-time polymerase chain reaction were used to assess inflammatory markers, tight-junction proteins, and cell death. RESULTS: In the DSS-induced colitis model, imatinib treatment exerted protective effects by attenuating weight loss, restoring colon length, reducing spleen weight, and improving the DAI score and histological lesions. Additionally, imatinib reduced the level of proinflammatory cytokines, including TNF-α, IL-6, and IL-1ß. Furthermore, imatinib treatment restored tight-junction integrity and decreased the expression of apoptosis marker proteins. CONCLUSION: Overall, imatinib treatment significantly alleviated the symptoms of DSS-induced colitis by influencing the expression of proinflammatory cytokines, tight junction proteins, and apoptotic markers in mice. These findings highlight imatinib as a potential therapeutic candidate for IBD.
Asunto(s)
Apoptosis , Colitis , Citocinas , Sulfato de Dextran , Modelos Animales de Enfermedad , Mesilato de Imatinib , Animales , Mesilato de Imatinib/farmacología , Sulfato de Dextran/efectos adversos , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Colitis/metabolismo , Ratones , Apoptosis/efectos de los fármacos , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Mediadores de Inflamación/metabolismo , BiomarcadoresRESUMEN
Therapeutic drug monitoring (TDM) of imatinib (IM) in cancer therapy offers the potential to improve treatment efficacy while minimizing toxicity. There was a significant correlation between unbound concentration and clinical response and toxicity, compared with total plasma concentrations, and the quantification of unbound IM and its metabolite, N-desmethyl imatinib (NDI) are of interest for TDM. However, traditional unbound drug separation methods have shortcomings, especially are susceptible to non-specific binding (NSB) of drugs to the polymer-constructed components of filter membranes, which are difficult to avoid at present. Hence it is necessary to developed a reliable separation method for the analysis of the unbound fraction of IM and NDI in TDM. We developed and validated an hollow fiber solid phase microextraction (HF-SPME) method coupled with high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) that to measure unbound IM and NDI concentration in human plasma. It used the NSB phenomenon and solve the NSB problem. The preparation procedure only involves a common vortex and ultrasonication without dilution of samples and modification of membrane. A total of 50 chronic myeloid leukemia (CML) patients were enrolled in our study. The relationship between the unbound and total concentrations for IM and NDI, as well as the concentration ratios of NDI to IM in 50 clinical plasma samples were investigated. The extraction recovery is high to 95.5-106â¯% with validation parameters for the methodological results were all excellent. There were both a poor linear relationship between the unbound and total concentrations for IM (r2=0.504) and NDI (r2=0.201) in 50 clinical plasma samples. The unbound concentration ratios of NDI to IM varied widely in CML patients. The determination of unbound IM and NDI concentration is meaningful and necessary. The developed HF-SPME method is simple, accurate and precise that could be used to measure unbound IM and NDI concentration in clinical TDM.
Asunto(s)
Monitoreo de Drogas , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Microextracción en Fase Sólida , Espectrometría de Masas en Tándem , Humanos , Mesilato de Imatinib/sangre , Mesilato de Imatinib/farmacocinética , Microextracción en Fase Sólida/métodos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Monitoreo de Drogas/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Femenino , Masculino , Persona de Mediana Edad , Adulto , Reproducibilidad de los ResultadosRESUMEN
Glucocorticoids (GCs) are known to stimulate pancreatic beta (ß)-cell apoptosis via several mechanisms, including oxidative stress. Our previous study suggested an increase in dexamethasone-induced pancreatic ß-cell apoptosis via a reduction of glutathione S-transferase P1 (GSTP1), which is an antioxidant enzyme. Imatinib, which is a tyrosine kinase inhibitor, also exerts antioxidant effect. This study aims to test our hypothesis that imatinib would prevent pancreatic ß-cell apoptosis induced by dexamethasone via increased GSTP1 expression and reduced oxidative stress. Our results revealed that dexamethasone significantly increased apoptosis in INS-1 cells when compared to the control, and that imatinib significantly decreased INS-1 cell apoptosis induced by dexamethasone. Moreover, dexamethasone significantly increased superoxide production in INS-1 cells when compared to the control; however, imatinib, when combined with dexamethasone, significantly reduced superoxide production in INS-1 cells. Dexamethasone significantly decreased GSTP1, p-ERK1/2, and BCL2 protein expression, but significantly increased p-JNK, p-p38, and BAX protein expression in INS-1 cells-all compared to control. Importantly, imatinib significantly ameliorated the effect of dexamethasone on the expression of GSTP1, p-ERK1/2, p-JNK, p-p38 MAPK, BAX, and BCL2. Furthermore-6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), which is a GSTP1 inhibitor, neutralized the protective effect of imatinib against pancreatic ß-cell apoptosis induced by dexamethasone. In conclusion, imatinib decreases pancreatic ß-cell apoptosis induced by dexamethasone via increased GSTP1 expression and reduced oxidative stress.
Asunto(s)
Apoptosis , Dexametasona , Gutatión-S-Transferasa pi , Mesilato de Imatinib , Células Secretoras de Insulina , Estrés Oxidativo , Mesilato de Imatinib/farmacología , Dexametasona/farmacología , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Gutatión-S-Transferasa pi/metabolismo , Animales , Ratas , Línea Celular , Superóxidos/metabolismoRESUMEN
BACKGROUND: Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME. METHODS: CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T. RESULTS: The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α. CONCLUSIONS: These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.