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Redox Biology Sep 2023Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent...
Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with G to elicit intracellular Ca flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced ferroptosis in human cardiomyocytes. Thus, PGE/EP1 axis protects cardiomyocytes from DOX-induced ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.
Topics: Animals; Humans; Mice; Apoptosis; Dinoprostone; Doxorubicin; Ferroptosis; Myocytes, Cardiac; NF-E2-Related Factor 2
PubMed: 37531930
DOI: 10.1016/j.redox.2023.102825 -
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 Advances Aug 2023Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia... (Randomized Controlled Trial)
Randomized Controlled Trial
Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia (AML); to date, there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). A total of 189 patients were randomized (median age, 56 years). Per clinical criteria, 49% of patients had de novo AML, 20% had secondary AML, and 30% had high-risk MDS. MDS-related cytogenetics were present in 73% of the patients, with a complex karyotype in 49%. TP53 was the most common mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 (44%) patients. The overall response rate (CR + CRi) after course 2 was 64% and 76% for CPX-351 and FLAG-Ida, respectively. There was no difference in OS (13.3 months vs 11.4 months) or event-free survival in multivariable analysis. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months). There was no difference between the treatment arms in patients with clinically defined secondary AML or those with MDS-related cytogenetic abnormalities; however, an exploratory subgroup of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months). In conclusion, the OS of younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.
Topics: Adult; Humans; Aged; Middle Aged; Daunorubicin; Cytarabine; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Karyotype; United Kingdom
PubMed: 37171402
DOI: 10.1182/bloodadvances.2023010276 -
Nature Communications Jul 2023A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. Here,...
A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. Here, we report an improved MYC-driven hepatoblastoma-like murine model that recapitulates the pathological features of embryonal type of hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and spatial transcriptomics identify distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we map cancer dependency genes using CRISPR-Cas9 screening and identify druggable targets shared with human hepatoblastoma (e.g., CDK7, CDK9, PRMT1, PRMT5). Our screen also reveals oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is critical for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identifies modifiers whose loss-of-function synergizes with (e.g., PRKDC) or antagonizes (e.g., apoptosis genes) the effect of chemotherapy. The combination of PRKDC inhibition and doxorubicin-based chemotherapy greatly enhances therapeutic efficacy. These studies provide a set of resources including disease models suitable for identifying and validating potential therapeutic targets in human high-risk hepatoblastoma.
Topics: Humans; Animals; Mice; Hepatoblastoma; Liver Neoplasms; Doxorubicin; Cell Line; Oncogenes; Protein-Arginine N-Methyltransferases; Repressor Proteins
PubMed: 37414763
DOI: 10.1038/s41467-023-39717-6 -
Redox Biology Apr 2024Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key...
Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key molecular mechanism of DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ), an iron chelator, is the only drug approved by the FDA for reducing DIC, but it has many side effects and cannot be used as a preventive drug in clinical practice. Single-nucleus RNA sequencing (snRNA-seq) analysis identified myocardial and epithelial cells that are susceptible to DOX-induced ferroptosis. The glutathione peroxidase 4 (GPX4) activator selenomethione (SeMet) significantly reduced polyunsaturated fatty acids (PUFAs) and oxidized lipid levels in vitro. Consistently, SeMet significantly decreased DOX-induced lipid peroxidation in H9C2 cells and mortality in C57BL/6 mice compared to DXZ, ferrostatin-1, and normal saline. SeMet can effectively reduce serum markers of cardiac injury in C57BL/6 mice and breast cancer patients. Depletion of the GPX4 gene in C57BL/6 mice resulted in an increase in polyunsaturated fatty acid (PUFA) levels and eliminated the protective effect of SeMet against DIC. Notably, SeMet exerted antitumor effects on breast cancer models with DOX while providing cardiac protection for the same animal without detectable toxicities. These findings suggest that pharmacological activation of GPX4 is a valuable and promising strategy for preventing the cardiotoxicity of doxorubicin.
Topics: Humans; Mice; Animals; Female; Phospholipid Hydroperoxide Glutathione Peroxidase; Cardiotoxicity; Mice, Inbred C57BL; Cardiomyopathies; Doxorubicin; Fatty Acids, Unsaturated; Breast Neoplasms
PubMed: 38232458
DOI: 10.1016/j.redox.2023.103024 -
Nature Communications Jun 2023DNA derived from chemotherapeutics-killed tumor cells is one of the most important damage-associated molecular patterns that can activate the cGAS-STING (cyclic GMP-AMP...
DNA derived from chemotherapeutics-killed tumor cells is one of the most important damage-associated molecular patterns that can activate the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway in antigen-presenting cells (APCs) and promote antitumor immunity. However, conventional chemotherapy displays limited tumor cell killing and ineffective transfer of stable tumor DNA to APCs. Here we show that liposomes loaded with an optimized ratio of indocyanine green and doxorubicin, denoted as LID, efficiently generate reactive oxygen species upon exposure to ultrasound. LID plus ultrasound enhance the nuclear delivery of doxorubicin, induce tumor mitochondrial DNA oxidation, and promote oxidized tumor mitochondrial DNA transfer to APCs for effective activation of cGAS-STING signaling. Depleting tumor mitochondrial DNA or knocking out STING in APCs compromises the activation of APCs. Furthermore, systemic injection of LID plus ultrasound over the tumor lead to targeted cytotoxicity and STING activation, eliciting potent antitumor T cell immunity, which upon the combination with immune checkpoint blockade leads to regression of bilateral MC38, CT26, and orthotopic 4T1 tumors in female mice. Our study sheds light on the importance of oxidized tumor mitochondrial DNA in STING-mediated antitumor immunity and may inspire the development of more effective strategies for cancer immunotherapy.
Topics: Female; Animals; Mice; DNA, Mitochondrial; Liposomes; Mitochondria; Immunotherapy; DNA, Neoplasm; Chromogranin A; Doxorubicin
PubMed: 37391428
DOI: 10.1038/s41467-023-39607-x -
Blood Nov 2023Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a...
Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.
Topics: Humans; Aged; Gemtuzumab; Daunorubicin; Antibodies, Monoclonal, Humanized; Cytarabine; Leukemia, Myeloid, Acute; United Kingdom; Aminoglycosides; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37595359
DOI: 10.1182/blood.2023020630 -
Drug Resistance Updates : Reviews and... Jul 2023Neoadjuvant chemotherapy (NAC) is the primary preoperative therapy for breast cancer. The luminal subtype of breast cancer shows less NAC response than the basal...
AIMS
Neoadjuvant chemotherapy (NAC) is the primary preoperative therapy for breast cancer. The luminal subtype of breast cancer shows less NAC response than the basal subtype, with an inefficient NAC treatment effect. Understanding of the molecular and cellular mechanisms responsible for this chemoresistance is an important issue when determining optimal treatment.
METHODS
Doxorubicin-induced apoptosis and ferroptosis was investigated using cytotoxicity, western blotting, and flow cytometry assays. The role of GATA3 in modulating doxorubicin-induced cell death was investigated both in vitro and in vivo. RNA-seq, qPCR, ChIP, and luciferase assay and association analyses were performed to investigate the regulation of CYB5R2 by GATA3. The function of GATA3 and CYB5R2 in regulating doxorubicin-induced ferroptosis was evaluated with iron, ROS, and lipid peroxidation detection assays. Immunohistochemistry was performed for results validation.
RESULTS
Doxorubicin-induced basal breast cancer cell death is dependent on iron-mediated ferroptosis. Overexpression of the luminal signature transcriptional factor GATA3 mediates doxorubicin resistance. GATA3 promotes cell viability by decreasing ferroptosis-related gene CYB5R2 expression and by maintaining iron homeostasis. Analyzing data from the public and our cohorts demonstrates that GATA3 and CYB5R2 are associated with NAC response.
CONCLUSIONS
GATA3 promotes doxorubicin resistance by inhibiting CYB5R2-mediated iron metabolism and ferroptosis. Therefore, patients with breast cancer who display high GATA3 expression do not benefit from doxorubicin-based NAC regimens.
Topics: Humans; Female; Breast Neoplasms; Doxorubicin; Apoptosis; Iron; Catalysis; GATA3 Transcription Factor
PubMed: 37230023
DOI: 10.1016/j.drup.2023.100974 -
Biomedicine & Pharmacotherapy =... Oct 2023With the progression of tumor treatment, the 5-year survival rate of breast cancer is close to 90%. Cardiovascular toxicity caused by chemotherapy has become a vital... (Review)
Review
With the progression of tumor treatment, the 5-year survival rate of breast cancer is close to 90%. Cardiovascular toxicity caused by chemotherapy has become a vital factor affecting the survival of patients with breast cancer. Anthracyclines, such as doxorubicin, are still some of the most effective chemotherapeutic agents, but their resulting cardiotoxicity is generally considered to be progressive and irreversible. In addition to anthracyclines, platinum- and alkyl-based antitumor drugs also demonstrate certain cardiotoxic effects. Targeted drugs have always been considered a relatively safe option. However, in recent years, some random clinical trials have observed the occurrence of subclinical cardiotoxicity in targeted antitumor drug users, which may be related to the effects of targeted drugs on the angiotensin converting enzyme, angiotensin receptor and β receptor. The use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers may prevent clinical cardiotoxicity. This article reviews the toxicity and mechanisms of current clinical anti-breast cancer drugs and proposes strategies for preventing cardiovascular toxicity to provide recommendations for the clinical prevention and treatment of chemotherapy-related cardiomyopathy.
Topics: Humans; Female; Cardiotoxicity; Breast Neoplasms; Cardiomyopathies; Doxorubicin; Anthracyclines
PubMed: 37647693
DOI: 10.1016/j.biopha.2023.115373 -
The Lancet. Haematology Nov 2023Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive... (Randomized Controlled Trial)
Randomized Controlled Trial
10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.
BACKGROUND
Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.
METHODS
This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m) was administered over the first 3 days and cytarabine (200 mg/m) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants.
FINDINGS
Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group.
INTERPRETATION
10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics.
FUNDING
Janssen Pharmaceuticals.
Topics: Humans; Middle Aged; Aged; Decitabine; Leukemia, Myeloid, Acute; Cytarabine; Daunorubicin; Transplantation, Homologous; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37914482
DOI: 10.1016/S2352-3026(23)00273-9