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Nature Medicine Aug 2018Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may...
Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.
Topics: Adipose Tissue; Animals; Cell Transplantation; Cellular Senescence; Cytokines; Dasatinib; Diet, High-Fat; Inflammation Mediators; Longevity; Mice, Inbred C57BL; Quercetin; Stress, Physiological; Survival Analysis
PubMed: 29988130
DOI: 10.1038/s41591-018-0092-9 -
Aging Cell Feb 2023Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic...
Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low-grade inflammation and a host of age-related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood. Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age-related increase in senescence-associated β-galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04). This treatment also suppressed age-related increase in the expression of a subset of pro-inflammatory SASP genes (mcp1, tnf-α, il-1α, il-1β, il-6, cxcl2, and cxcl10), crown-like structures, abundance of T cells and macrophages in pgWAT (all p ≤ 0.04). In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers. Although we did not observe an age-related difference in glucose tolerance, D&Q treatment improved fasting blood glucose (p = 0.001) and glucose tolerance (p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin-stimulated suppression of plasma NEFAs (p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance (p = 0.006). Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.
Topics: Mice; Animals; Dasatinib; Cellular Senescence; Quercetin; Senotherapeutics; Adipose Tissue; Inflammation; Glucose
PubMed: 36637079
DOI: 10.1111/acel.13767 -
Blood Aug 2016Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another...
Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Dasatinib; Female; Fusion Proteins, bcr-abl; Humans; Male; Middle Aged; Mutation; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Prospective Studies; Protein Kinase Inhibitors
PubMed: 27121472
DOI: 10.1182/blood-2016-02-700153 -
The Journals of Gerontology. Series A,... Oct 2021Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities, and mortality caused by tissue inflammation and damage. Senescent...
Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities, and mortality caused by tissue inflammation and damage. Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders. The senolytic drug combination, Dasatinib plus Quercetin (D+Q), is known to reduce senescent cell abundance in aged mice. However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown. Here, we examine the effect of D+Q on senescence (p16Ink4a and p21Cip1) and inflammation (Cxcl1, Il1β, Il6, Mcp1, and Tnfα) markers in small (ileum) and large (caecum and colon) intestine in aged mice (n = 10) compared to age-matched placebo-treated mice (n = 10). Additionally, we examine microbial composition along the intestinal tract in these mice. D+Q-treated mice show significantly lower senescent cell (p16 and p21 expression) and inflammatory (Cxcl1, Il1β, Il6, Mcp1, and Tnfα expression) burden in small and large intestine compared with control mice. Further, we find specific microbial signatures in ileal, cecal, colonic, and fecal regions that are distinctly modulated by D+Q, with modulation being most prominent in small intestine. Further analyses reveal specific correlation of senescence and inflammation markers with specific microbial signatures. Together, these data demonstrate that the senolytic treatment reduces intestinal senescence and inflammation while altering specific microbiota signatures and suggest that the optimized senolytic regimens might improve health via reducing intestinal senescence, inflammation, and microbial dysbiosis in older subjects.
Topics: Animals; Biomarkers; Cellular Senescence; Dasatinib; Gastrointestinal Microbiome; Inflammation; Interleukin-6; Intestines; Mice; Quercetin; Senotherapeutics; Tumor Necrosis Factor-alpha
PubMed: 33406219
DOI: 10.1093/gerona/glab002 -
Blood May 2022When imatinib, the first tyrosine kinase inhibitor (TKI) developed for use in chronic myelogenous leukemia (CML), was approved in 2001, the treatment of this disease was... (Review)
Review
When imatinib, the first tyrosine kinase inhibitor (TKI) developed for use in chronic myelogenous leukemia (CML), was approved in 2001, the treatment of this disease was forever changed. Significant reductions in the molecular burden of disease were seen with the first-generation TKI imatinib and, with the addition of dasatinib (2006), nilotinib (2007), bosutinib (2012), and ponatinib (2013), deeper and more rapid reductions were noted. Physicians could begin to tailor TKI therapy to individual patients, and patients who did not respond to or could not tolerate first-line therapy now had options. Importantly, the number of patients who developed accelerated or blast phase disease decreased dramatically. Research in CML continues to evolve; by presenting illustrative cases, this article reviews some of the newer aspects of clinical care in this disease. Updated information regarding bosutinib and asciminib, the latter currently in clinical trials, will be presented; bosutinib is of particular interest as the drug's transit through the United States Food and Drug Administration highlights the question of what is considered optimal response to TKI therapy. The challenge of understanding the cardiac safety data of ponatinib and the unique dosing schedule based on individual response will be discussed. Lastly, two cases will focus on features of TKI treatment that, remarkably, have become part of the treatment algorithm: family planning for women with CML and stopping therapy after meeting a specific treatment milestone.
Topics: Antineoplastic Agents; Dasatinib; Female; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Protein Kinase Inhibitors
PubMed: 34529784
DOI: 10.1182/blood.2021011722 -
Journal of Clinical Oncology : Official... Jul 2016We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib.
PATIENTS AND METHODS
Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260).
RESULTS
At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms.
CONCLUSION
These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.
Topics: Adult; Aged; Dasatinib; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myeloid, Chronic-Phase; Middle Aged; Mutation
PubMed: 27217448
DOI: 10.1200/JCO.2015.64.8899 -
Journal of Neuroinflammation Oct 2019The FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML). However, the effects of dasatinib on microglial...
BACKGROUND
The FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML). However, the effects of dasatinib on microglial and/or astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail.
METHODS
BV2 microglial cells, primary astrocytes, or primary microglial cells were treated with dasatinib (100 or 250 nM) or vehicle (1% DMSO) for 30 min or 2 h followed by lipopolysaccharide (LPS; 200 ng/ml or 1 μg/ml) or PBS for 5.5 h. RT-PCR, real-time PCR; immunocytochemistry; subcellular fractionation; and immunohistochemistry were subsequently conducted to determine the effects of dasatinib on LPS-induced neuroinflammation. In addition, wild-type mice were injected with dasatinib (20 mg/kg, intraperitoneally (i.p.) daily for 4 days or 20 mg/kg, orally administered (p.o.) daily for 4 days or 2 weeks) or vehicle (4% DMSO + 30% polyethylene glycol (PEG) + 5% Tween 80), followed by injection with LPS (10 mg/kg, i.p.) or PBS. Then, immunohistochemistry was performed, and plasma IL-6, IL-1β, and TNF-α levels were analyzed by ELISA.
RESULTS
Dasatinib regulates LPS-induced proinflammatory cytokine and anti-inflammatory cytokine levels in BV2 microglial cells, primary microglial cells, and primary astrocytes. In BV2 microglial cells, dasatinib regulates LPS-induced proinflammatory cytokine levels by regulating TLR4/AKT and/or TLR4/ERK signaling. In addition, intraperitoneal injection and oral administration of dasatinib suppress LPS-induced microglial/astrocyte activation, proinflammatory cytokine levels (including brain and plasma levels), and neutrophil rolling in the brains of wild-type mice.
CONCLUSIONS
Our results suggest that dasatinib modulates LPS-induced microglial and astrocytic activation, proinflammatory cytokine levels, and neutrophil rolling in the brain.
Topics: Animals; Animals, Newborn; Astrocytes; Cells, Cultured; Dasatinib; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microglia; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor
PubMed: 31655606
DOI: 10.1186/s12974-019-1561-x -
Clinical Lymphoma, Myeloma & Leukemia Feb 2017Dasatinib has demonstrated durable clinical responses in patients, both as first-line and subsequent lines of therapy. Dasatinib use can result in pleural effusion in... (Review)
Review
Dasatinib has demonstrated durable clinical responses in patients, both as first-line and subsequent lines of therapy. Dasatinib use can result in pleural effusion in some patients, occurring any time during treatment and commonly characterized as mild to moderate in severity. Early identification of symptoms is essential in the proper management of pleural effusion. Prompt confirmation of diagnosis and management of pleural effusion can minimize morbidity and maximize the ability to preserve long-term clinical benefits with dasatinib. Here, we provide guidance on early identification and management of dasatinib-related pleural effusion.
Topics: Antineoplastic Agents; Dasatinib; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pleural Effusion
PubMed: 28082112
DOI: 10.1016/j.clml.2016.09.012 -
Science (New York, N.Y.) Jul 2021The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2...
The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.
Topics: Aging; Animals; COVID-19; Cell Line; Cellular Senescence; Coronavirus Infections; Dasatinib; Female; Flavonols; Gene Expression Regulation; Humans; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Murine hepatitis virus; Pathogen-Associated Molecular Pattern Molecules; Quercetin; Receptors, Coronavirus; Specific Pathogen-Free Organisms; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 34103349
DOI: 10.1126/science.abe4832 -
Current Hematologic Malignancy Reports Oct 2022Due to lack of pediatric-specific data, the management of chronic myeloid leukemia (CML) in pediatric, adolescents, and young adults is guided by adult CML... (Review)
Review
PURPOSE OF REVIEW
Due to lack of pediatric-specific data, the management of chronic myeloid leukemia (CML) in pediatric, adolescents, and young adults is guided by adult CML evidence-based recommendations. Pediatric CML presents differently than adult CML and is often a more aggressive disease with different biological and host factors, yet there is sparse literature on how to address those differences.
RECENT FINDINGS
Over the past two decades, tyrosine kinase inhibitors (TKIs) have changed the way CML is treated. There are currently three FDA-approved TKIs (imatinib, dasatinib, and nilotinib) for pediatric patients. When choosing which TKI to begin treatment with, there are many factors that should be considered on a case-to-case basis to obtain optimal outcomes. The safety profiles for long-term TKI use in pediatrics require further study. Unlike adults, children are still actively growing during TKI use, and the effect on development can be detrimental. TKI therapy is not recommended during pregnancy with variable but significant risk of fetal abnormalities and miscarriage, warranting counseling for young female patients prior to beginning TKIs. Attempts for treatment-free remission (TFR) by planned TKI cessation in eligible adult patients in deep and sustained molecular remission are now done as a standard of practice. However, data is sparse in the pediatric population. There is currently an ongoing Children's Oncology Group (COG) study to determine the feasibility of TFR as a treatment goal. Further research and additional pediatric trials are needed to characterize the unique aspects of CML in children and adolescents and optimize outcomes.
Topics: Adolescent; Child; Dasatinib; Female; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Young Adult
PubMed: 35920965
DOI: 10.1007/s11899-022-00673-5