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Nucleic Acids Research Aug 2019Cellular senescence, an integral component of aging and cancer, arises in response to diverse triggers, including telomere attrition, macromolecular damage and...
Cellular senescence, an integral component of aging and cancer, arises in response to diverse triggers, including telomere attrition, macromolecular damage and signaling from activated oncogenes. At present, senescent cells are identified by the combined presence of multiple traits, such as senescence-associated protein expression and secretion, DNA damage and β-galactosidase activity; unfortunately, these traits are neither exclusively nor universally present in senescent cells. To identify robust shared markers of senescence, we have performed RNA-sequencing analysis across eight diverse models of senescence triggered in human diploid fibroblasts (WI-38, IMR-90) and endothelial cells (HUVEC, HAEC) by replicative exhaustion, exposure to ionizing radiation or doxorubicin, and expression of the oncogene HRASG12V. The intersection of the altered transcriptomes revealed 50 RNAs consistently elevated and 18 RNAs consistently reduced across all senescence models, including many protein-coding mRNAs and some non-coding RNAs. We propose that these shared transcriptome profiles will enable the identification of senescent cells in vivo, the investigation of their roles in aging and malignancy and the development of strategies to target senescent cells therapeutically.
Topics: Aging; Antibiotics, Antineoplastic; Cell Line; Cells, Cultured; Cellular Senescence; Doxorubicin; Endothelial Cells; Fibroblasts; Humans; Neoplasms; RNA, Messenger; Radiation, Ionizing; Sequence Analysis, RNA; Transcriptome
PubMed: 31251810
DOI: 10.1093/nar/gkz555 -
International Journal of Biological... 2022Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its... (Review)
Review
Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its use places survivors at risk for cardiotoxicity. Many studies have demonstrated that multiple factors are involved in DOX-induced acute cardiotoxicity. Among them, oxidative stress and cell death predominate. In this review, we provide a comprehensive overview of the mechanisms underlying the source and effect of free radicals and dependent cell death pathways induced by DOX. Hence, we attempt to explain the cellular mechanisms of oxidative stress and cell death that elicit acute cardiotoxicity and provide new insights for researchers to discover potential therapeutic strategies to prevent or reverse doxorubicin-induced cardiotoxicity.
Topics: Acute Disease; Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Cell Death; Doxorubicin; Humans; Neoplasms; Oxidative Stress
PubMed: 35002523
DOI: 10.7150/ijbs.65258 -
JAMA Aug 2023Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use.
OBJECTIVE
To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction.
DESIGN, SETTING, AND PARTICIPANTS
Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022.
INTERVENTIONS
Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months.
MAIN OUTCOMES AND MEASURES
The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months.
RESULTS
Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups.
CONCLUSIONS AND RELEVANCE
Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02943590.
Topics: Female; Humans; Middle Aged; Anthracyclines; Antibiotics, Antineoplastic; Atorvastatin; Double-Blind Method; Heart Failure; Retrospective Studies; Stroke Volume; Ventricular Function, Left; Cardiovascular Agents; Lymphoma; Heart Diseases; Follow-Up Studies; Male; Adult; Aged
PubMed: 37552303
DOI: 10.1001/jama.2023.11887 -
Circulation Research Mar 2020Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly... (Review)
Review
Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiomyopathies; Doxorubicin; Humans; Mitochondria, Heart; Mitophagy; Reactive Oxygen Species; Superoxides
PubMed: 32213135
DOI: 10.1161/CIRCRESAHA.119.314681 -
Biomedicine & Pharmacotherapy =... Jul 2021Doxorubicin (Dox) is a secondary metabolite of the mutated strain of Streptomyces peucetius var. Caesius and belongs to the anthracyclines family. The anti-cancer... (Review)
Review
Doxorubicin (Dox) is a secondary metabolite of the mutated strain of Streptomyces peucetius var. Caesius and belongs to the anthracyclines family. The anti-cancer activity of Dox is mainly exerted through the DNA intercalation and inhibiting topoisomerase II enzyme in fast-proliferating tumors. However, Dox causes cumulative and dose-dependent cardiotoxicity, which results in increased risks of mortality among cancer patients and thus limiting its wide clinical applications. There are several mechanisms has been proposed for doxorubicin-induced cardiotoxicity and oxidative stress, free radical generation and apoptosis are most widely reported. Apart from this, other mechanisms are also involved in Dox-induced cardiotoxicity such as impaired mitochondrial function, a perturbation in iron regulatory protein, disruption of Ca homeostasis, autophagy, the release of nitric oxide and inflammatory mediators and altered gene and protein expression that involved apoptosis. Dox also causes downregulation of DNA methyltransferase 1 (DNMT1) enzyme activity which leads to a reduction in the DNA methylation process. This hypomethylation causes dysregulation in the mitochondrial genes like peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1-alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) unit in the heart. Apart from DNA methylation, Dox treatment also alters the micro RNAs levels and histone deacetylase (HDAC) activity. Therefore, in the current review, we have provided a detailed update on the current understanding of the pathological mechanisms behind the well-known Dox-induced cardiotoxicity. Further, we have provided some of the most plausible pharmacological strategies which have been tested against Dox-induced cardiotoxicity.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiotoxicity; Doxorubicin; Humans; Mitochondria, Heart; Oxidative Stress
PubMed: 34243633
DOI: 10.1016/j.biopha.2021.111708 -
Journal of Clinical Oncology : Official... Nov 2021Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm,...
PURPOSE
Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor -sirolimus (AMPECT, NCT02494570).
PATIENTS AND METHODS
Patients with malignant PEComa were treated with -sirolimus 100 mg/m intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis.
RESULTS
Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range, 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a mutation achieved a confirmed response versus 2 of 16 (13%) without mutation ( < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred.
CONCLUSION
-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that -sirolimus represents an important new treatment option for this disease.
Topics: Adult; Aged; Albumins; Antibiotics, Antineoplastic; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nanoparticles; Neoplasm Metastasis; Perivascular Epithelioid Cell Neoplasms; Prognosis; Prospective Studies; Sirolimus; Survival Rate
PubMed: 34637337
DOI: 10.1200/JCO.21.01728 -
European Journal of Cancer (Oxford,... May 2023Anthracyclines have contributed significantly to remarkable improvements in overall survival and are regarded as the most effective cytostatic drug for cancer treatment... (Review)
Review
Anthracyclines have contributed significantly to remarkable improvements in overall survival and are regarded as the most effective cytostatic drug for cancer treatment in various malignancies. However, anthracyclines are a significant cause of acute and chronic cardiotoxicity in cancer patients, and long-term cardiotoxicity can lead to death in about one-third of patients. Several molecular pathways have been implicated in the development of anthracycline-induced cardiotoxicity, although the underlying mechanisms of some molecular pathways are not fully elucidated. It is now generally believed that anthracycline-induced reactive oxygen species (resulting from intracellular metabolism of anthracyclines) and drug-induced inhibition of topoisomerase II beta are the key mechanisms responsible for the cardiotoxicity. To prevent cardiotoxicity, several strategies are being followed: (i) angiotensin-converting enzyme inhibitors, sartans, beta-blockers, aldosterone antagonists, and statins; (ii) iron chelators; and (iii) by development of new anthracycline derivatives with little or no cardiotoxicity. This review will discuss clinically evaluated doxorubicin analogues that were developed as potentially non-cardiotoxic anticancer agents and include recent development of a novel liposomal anthracycline (L-Annamycin) for the treatment of soft-tissue sarcoma metastatic to the lung and acute myelogenous leukaemia.
Topics: Humans; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Neoplasms; Angiotensin-Converting Enzyme Inhibitors
PubMed: 36966697
DOI: 10.1016/j.ejca.2023.02.019 -
Molecular Aspects of Medicine Oct 2023Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by... (Review)
Review
Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action. The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance.
Topics: Humans; Anthracyclines; Drug Resistance, Neoplasm; Doxorubicin; Antibiotics, Antineoplastic; Neoplasms
PubMed: 37515939
DOI: 10.1016/j.mam.2023.101205 -
Blood Apr 2021Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA...
Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.
Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; DNA Methylation; Depsipeptides; Female; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Mutation; Treatment Outcome
PubMed: 33171487
DOI: 10.1182/blood.2020009004 -
Journal of Clinical Oncology : Official... Apr 2023For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
PURPOSE
For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
METHODS
Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status.
RESULTS
From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m.
CONCLUSION
Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.
Topics: Young Adult; Child; Humans; Aged; Dexrazoxane; Cancer Survivors; Doxorubicin; Antibiotics, Antineoplastic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Osteosarcoma; Bone Neoplasms
PubMed: 36669148
DOI: 10.1200/JCO.22.02423