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GeroScience Oct 2023Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first...
Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow estimation of the main translatable effects of the senolytic combination dasatinib (D) and quercetin (Q), with and without caloric restriction (CR). A multi-systemic survey of age-related changes, including those on immune cells, adipose tissue, the microbiome, and biomarkers of systemic organ and metabolic health are reported. Age-, weight-, sex-, and glycemic control-matched NHPs (D + Q, n = 9; vehicle [VEH] n = 7) received two consecutive days of D + Q (5 mg/kg + 50 mg/kg) monthly for 6 months, where in month six, a 10% CR was implemented in both D + Q and VEH NHPs to induce equal weight reductions. D + Q reduced senescence marker gene expressions in adipose tissue and circulating PAI-1 and MMP-9. Improvements were observed in immune cell types with significant anti-inflammatory shifts and reductions in microbial translocation biomarkers, despite stable microbiomes. Blood urea nitrogen showed robust improvements with D + Q. CR resulted in significant positive body composition changes in both groups with further improvement in immune cell profiles and decreased GDF15 (p = 0.05), and the interaction of D + Q and CR dramatically reduced glycosylated hemoglobin A1c (p = 0.03). This work indicates that 6 months of intermittent D + Q exposure is safe and may combat inflammaging via immune benefits and improved intestinal barrier function. We also saw renal benefits, and with CR, improved metabolic health. These data are intended to provide direction for the design of larger controlled intervention trials in older patients.
Topics: Animals; Humans; Middle Aged; Aged; Dasatinib; Quercetin; Senotherapeutics; Clinical Trials as Topic; Aging; Inflammation; Biomarkers; Primates
PubMed: 37261678
DOI: 10.1007/s11357-023-00830-5 -
The Gulf Journal of Oncology Sep 2022Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used in the first- and second-line treatment of chronic myeloid leukemia (CML). Chylothorax is a... (Review)
Review
Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used in the first- and second-line treatment of chronic myeloid leukemia (CML). Chylothorax is a rare presentation that results in chyle leakage from the lymphatic system into the pleural space as a consequence of thoracic duct damage. Pleural effusion has been reported frequently in patients treated with Dasatinib however chylothorax has been rarely reported. Here we report an 18year old female presenting with chylothorax after 63 months of Dasatinib intake along with a review of the relevant literature. Currently there are no standard guidelines regarding the approach to chylothorax management after the initial discontinuation of Dasatinib. Since the TKI options after stopping Dasatinib are limited, and most patients would have already failed the trial of first generation TKI, we suggest implementing a complete treatment strategy for this patient population. Key words: chronic myeloid leukemia, Dasatinib, Pleural effusion, Chylothorax.
Topics: Female; Humans; Chylothorax; Dasatinib; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pleural Effusion; Adolescent
PubMed: 36448074
DOI: No ID Found -
Biogerontology Feb 2024Cellular senescence is characteristic of the development and progression of multiple age-associated diseases. Accumulation of senescent cells in the heart contributes to... (Review)
Review
Cellular senescence is characteristic of the development and progression of multiple age-associated diseases. Accumulation of senescent cells in the heart contributes to various age-related pathologies. Several compounds called senolytics have been designed to eliminate these cells within the tissues. In recent years, the use and study of senolytics increased, representing a promising field for finding accessible and safe therapies for cardiovascular disease (CVD) treatment. This mini-review discusses the changes in the aging heart and the participation of senescent cells in CVD, as well as the use of senolytics to prevent the progression of myocardial damage, mainly the effect of dasatinib and quercetin. In particular, the mechanisms and physiological effects of senolytics therapies in the aged heart are discussed.
Topics: Humans; Dasatinib; Quercetin; Senotherapeutics; Cardiovascular Diseases; Aging; Cellular Senescence
PubMed: 37747577
DOI: 10.1007/s10522-023-10068-5 -
The Lancet. Oncology Jul 2024Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the... (Randomized Controlled Trial)
Randomized Controlled Trial
Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial.
BACKGROUND
Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma.
METHODS
The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m on day 1, maintenance 1 mg/m on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m per day] and oral temozolomide [150 mg/m per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual.
FINDINGS
Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure).
INTERPRETATION
RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting.
FUNDING
Deutsche Krebshilfe.
Topics: Humans; Temozolomide; Irinotecan; Antineoplastic Combined Chemotherapy Protocols; Male; Female; Neuroblastoma; Child, Preschool; Child; Dasatinib; Adolescent; Neoplasm Recurrence, Local; Infant; Adult; Sirolimus; Young Adult; Germany; Drug Resistance, Neoplasm; Progression-Free Survival
PubMed: 38936379
DOI: 10.1016/S1470-2045(24)00202-X -
Internal Medicine (Tokyo, Japan) Aug 2022Objective Dasatinib, a second-generation tyrosine kinase inhibitor, is used for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute...
Objective Dasatinib, a second-generation tyrosine kinase inhibitor, is used for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It reportedly causes pulmonary arterial hypertension (PAH) and the dose-dependent induction of apoptosis in pulmonary endothelial cells. However, no report has yet discussed the relationship between dasatinib-induced PAH and drug dose. We therefore investigated the incidence of dasatinib-induced PAH and the relationship between dasatinib-PAH and drug dose in consecutive patients with CML and Ph+ ALL who took dasatinib. Methods The clinical data of 128 patients with CML (94 patients) and Ph+ ALL (34 patients) were retrospectively analyzed. Patients All patients (>17 years old) who received dasatinib from January 2009 to March 2020 at Jichi Medical University (Tochigi, Japan) were included. Patients who transferred within one month of starting dasatinib administration were excluded. Results Four (4.3%) and three (8.8%) patients developed pulmonary hypertension (PH), which was considered present when the transtricuspid pressure gradient was ≥40 mmHg, in the CML and ALL groups, respectively. No significant difference was observed between the PH onset and the administration period, cumulative dose, or daily dose of dasatinib. PH occurred in seven patients (5.5%), and the period from the start of dasatinib administration to the PH onset ranged from 7 to 39 (median: 28) months. No patients died from PH in either group. Conclusion Dasatinib-induced PAH does not occur time- or dose-dependently. When administering dasatinib, cardiovascular diagnostic modalities should be routinely checked, and PAH occurrence should be promptly detected.
Topics: Adolescent; Antineoplastic Agents; Dasatinib; Endothelial Cells; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 35022343
DOI: 10.2169/internalmedicine.8392-21 -
International Journal of Oral Science May 2023In dentistry, orthodontic root resorption is a long-lasting issue with no effective treatment strategy, and its mechanisms, especially those related to senescent cells,...
In dentistry, orthodontic root resorption is a long-lasting issue with no effective treatment strategy, and its mechanisms, especially those related to senescent cells, remain largely unknown. Here, we used an orthodontic intrusion tooth movement model with an L-loop in rats to demonstrate that mechanical stress-induced senescent cells aggravate apical root resorption, which was prevented by administering senolytics (a dasatinib and quercetin cocktail). Our results indicated that cementoblasts and periodontal ligament cells underwent cellular senescence (p21 or p16) and strongly expressed receptor activator of nuclear factor-kappa B (RANKL) from day three, subsequently inducing tartrate-resistant acid phosphatase (TRAP)-positive odontoclasts and provoking apical root resorption. More p21 senescent cells expressed RANKL than p16 senescent cells. We observed only minor changes in the number of RANKL non-senescent cells, whereas RANKL senescent cells markedly increased from day seven. Intriguingly, we also found cathepsin Kp21p16 cells in the root resorption fossa, suggesting senescent odontoclasts. Oral administration of dasatinib and quercetin markedly reduced these senescent cells and TRAP cells, eventually alleviating root resorption. Altogether, these results unveil those aberrant stimuli in orthodontic intrusive tooth movement induced RANKL early senescent cells, which have a pivotal role in odontoclastogenesis and subsequent root resorption. These findings offer a new therapeutic target to prevent root resorption during orthodontic tooth movement.
Topics: Rats; Animals; Root Resorption; Senotherapeutics; Stress, Mechanical; Dasatinib; Quercetin; Osteoclasts; Tooth Movement Techniques; Periodontal Ligament; RANK Ligand
PubMed: 37253719
DOI: 10.1038/s41368-023-00228-1 -
Journal of Natural Medicines Sep 2023Dasatinib is effective in the treatment of chronic and acute myeloid leukemia, which could cause the side effect of gastrointestinal bleeding by overdose or longtime...
Dasatinib is effective in the treatment of chronic and acute myeloid leukemia, which could cause the side effect of gastrointestinal bleeding by overdose or longtime use. Ruscogenin (RUS) from the traditional Chinese medicine Ophiopogon japonicas could protect endothelial microvascular barrier function. In this study, the therapeutic effect and underlying mechanisms of RUS were investigated on intestinal barrier dysfunction induced by dasatinib. Male C57BL/6 J mice were given three doses of dasatinib (70, 140, 210 mg/kg, ig) and RUS (3, 10, 30 μg/kg, ip) to explore the effect of dasatinib on intestinal barrier and the intervention of RUS. It was proved that dasatinib could reduce intestinal blood flow, inhibit phosphorylation of EGFR family member v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4 (ErbB4)/YES-associated protein (YAP) and activation of Rho-associated coiled coil-containing protein kinase (ROCK)/phosphorylation of (myosin light chain) MLC. RUS could significantly increase intestinal blood flow, improve intestinal injury, reduce Evans blue leakage and serum content of FITC-dextran 4 kDa, and increase the expression of connexin (ZO-1, Occludin and VE-cadherin). Meanwhile, the in vitro effect of RUS (0.01, 0.1, 1 μM) on the dysfunction of the endothelial barrier was observed in dasatinib (150 nM)-pretreated HUVECs. The results showed that RUS suppressed dasatinib-induced the leakage of Evans blue, and degradation of F-actin and connexin. Furthermore, RUS could significantly increase the phosphorylation of ErbB4 at Tyr1284 site and YAP at Ser397 site, and inhibit ROCK expression and phosphorylation of MLC at Ser19 site in vivo and in vitro. In conclusion, the present research proved that RUS could suppress the side effects of dasatinib-induced intestinal barrier dysfunction by regulating ErbB4/YAP and ROCK/MLC pathways.
Topics: Male; Mice; Animals; Dasatinib; Evans Blue; Mice, Inbred C57BL; Phosphorylation; rho-Associated Kinases
PubMed: 37347409
DOI: 10.1007/s11418-023-01715-9 -
Biogerontology Aug 2024The skin's protective functions are compromised over time by both endogenous and exogenous aging. Senescence is well-documented in skin phenotypes, such as wrinkling and...
The skin's protective functions are compromised over time by both endogenous and exogenous aging. Senescence is well-documented in skin phenotypes, such as wrinkling and sagging, a consequence of the senescence-associated secretory phenotype (SASP) that involves the accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling. Although therapeutic approaches for eliminating senescent cells from the skin are available, their efficacy remains unclear. Accordingly, we aimed to examine the effects of dasatinib in combination with quercetin (D + Q) on senescent human skin fibroblasts and aging human skin. Senescence was induced in human dermal fibroblasts (HDFs) using approaches such as long-term passaging, ionizing radiation, and doxorubicin treatment. The generated senescent cells were treated with D + Q or vehicle. Additionally, a mouse-human chimera model was generated by subcutaneously transplanting whole-skin grafts of aged individuals onto nude mice. Mouse models were administered D + Q or vehicle by oral gavage for 30 days. Subsequently, skin samples were harvested and stained for senescence-associated beta-galactosidase. Senescence-associated markers were assessed by western blotting, reverse transcription-quantitative PCR and histological analyses. Herein, D + Q selectively eliminated senescent HDFs in all cellular models of induced senescence. Additionally, D + Q-treated aged human skin grafts exhibited increased collagen density and suppression of the SASP compared with control grafts. No adverse events were observed during the study period. Collectively, D + Q could ameliorate skin aging through selective elimination of senescent dermal fibroblasts and suppression of the SASP. Our findings suggest that D + Q could be developed as an effective therapeutic approach for combating skin aging.
Topics: Dasatinib; Quercetin; Humans; Animals; Cellular Senescence; Fibroblasts; Skin Aging; Skin; Mice; Rejuvenation; Mice, Nude; Cells, Cultured; Senescence-Associated Secretory Phenotype; Female
PubMed: 38619669
DOI: 10.1007/s10522-024-10103-z -
Aging Cell May 2023We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral...
We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood-brain barrier (BBB) integrity, and prevented the age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function associated with impaired cognition. Senolytic treatments decreased senescence-associated secretory phenotype (SASP) and inflammatory cytokines/chemokines in the plasma (IL-1β, IP-10, and RANTES), with some markers more responsive to D + Q (TNFα) or ABT-263 (IFNγ, leptin, EGF). ABT-263 was more effective in decreasing senescence genes in the spleen. Both senolytic treatments decreased the expression of immune response and oxidative stress genes and increased the expression of synaptic genes in the dentate gyrus (DG). However, D + Q influenced twice as many genes as ABT-263. Relative to D + Q, the ABT-263 group exhibited increased expression of DG genes linked to cell death and negative regulation of apoptosis and microglial cell activation. Furthermore, D + Q was more effective at decreasing morphological markers of microglial activation. The results indicate that preserved cognition was associated with the removal of peripheral senescent cells, decreasing systemic inflammation that normally drives neuroinflammation, BBB breakdown, and impaired synaptic function. Dissimilarities associated with brain transcription indicate divergence in central mechanisms, possibly due to differential access.
Topics: Rats; Animals; Male; Senotherapeutics; Rats, Inbred F344; Cellular Senescence; Aging; Hippocampus; Dasatinib; Cognitive Dysfunction; Quercetin
PubMed: 36959691
DOI: 10.1111/acel.13817 -
American Journal of Respiratory Cell... Jul 2024Pulmonary arterial (PA) hypertension (PAH) is a severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic...
Pulmonary arterial (PA) hypertension (PAH) is a severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. We discovered a gene (Potassium channel subfamily K member 3; coding for outward K channel) variant in a patient with dasatinib-associated PAH and investigated the impact of this variant on KCNK3 function. Additionally, we assessed the effects of dasatinib exposure on KCNK3 expression. In control human PA smooth muscle cells (hPASMCs) and human pulmonary endothelial cells (hPECs), we evaluated the consequences of knockdown on cell migration, mitochondrial membrane potential, ATP production, and tube formation. Using mass spectrometry, we determined the KCNK3 interactome. Patch-clamp experiments revealed that the variant represents a loss-of-function variant. Dasatinib contributed to PA constriction by decreasing KCNK3 function and expression. In control hPASMCs, knockdown promotes mitochondrial membrane depolarization and glycolytic shift. Dasatinib exposure or knockdown reduced the number of caveolae in hPECs. Moreover, knockdown in control hPECs reduced migration, proliferation, and tubulogenesis. Using proximity labeling and mass spectrometry, we identified the KCNK3 interactome, revealing that KCNK3 interacts with various proteins across different cellular compartments. We identified a novel pathogenic variant in and showed that dasatinib downregulates KCNK3, emphasizing the relationship between dasatinib-associated PAH and KCNK3 dysfunction. We demonstrated that a loss of KCNK3-dependent signaling contributes to endothelial dysfunction in PAH and glycolytic switch of hPASMCs.
Topics: Dasatinib; Humans; Potassium Channels, Tandem Pore Domain; Endothelial Cells; Cell Movement; Pulmonary Arterial Hypertension; Membrane Potential, Mitochondrial; Myocytes, Smooth Muscle; Male; Pulmonary Artery; Nerve Tissue Proteins
PubMed: 38546978
DOI: 10.1165/rcmb.2023-0185OC