-
Cell Metabolism Jun 2023Fasting strategies are under active clinical investigation in patients receiving chemotherapy. Prior murine studies suggest that alternate-day fasting may attenuate... (Randomized Controlled Trial)
Randomized Controlled Trial
Fasting strategies are under active clinical investigation in patients receiving chemotherapy. Prior murine studies suggest that alternate-day fasting may attenuate doxorubicin cardiotoxicity and stimulate nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. In this study, human heart tissue from patients with doxorubicin-induced heart failure demonstrated increased nuclear TFEB protein. In mice treated with doxorubicin, alternate-day fasting or viral TFEB transduction increased mortality and impaired cardiac function. Mice randomized to alternate-day fasting plus doxorubicin exhibited increased TFEB nuclear translocation in the myocardium. When combined with doxorubicin, cardiomyocyte-specific TFEB overexpression provoked cardiac remodeling, while systemic TFEB overexpression increased growth differentiation factor 15 (GDF15) and caused heart failure and death. Cardiomyocyte TFEB knockout attenuated doxorubicin cardiotoxicity, while recombinant GDF15 was sufficient to cause cardiac atrophy. Our studies identify that both sustained alternate-day fasting and a TFEB/GDF15 pathway exacerbate doxorubicin cardiotoxicity.
Topics: Mice; Humans; Animals; Cardiotoxicity; Doxorubicin; Autophagy; Myocytes, Cardiac; Fasting; Heart Failure; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Lysosomes
PubMed: 36868222
DOI: 10.1016/j.cmet.2023.02.006 -
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 -
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 -
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 -
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 -
Redox Biology Aug 2023Doxorubicin (DOX) is commonly used for chemotherapy; however, its clinical value is extremely dampened because of the fatal cardiotoxicity. Leucine zipper protein 1...
OBJECTIVE
Doxorubicin (DOX) is commonly used for chemotherapy; however, its clinical value is extremely dampened because of the fatal cardiotoxicity. Leucine zipper protein 1 (LUZP1) plays critical roles in cardiovascular development, and this study is designed for determining its function and mechanism in DOX-induced cardiotoxicity.
METHODS
Cardiac-specific Luzp1 knockout (cKO) and transgenic (cTG) mice received a single or repeated DOX injections to establish acute and chronic cardiotoxicity. Biomarkers of inflammation, oxidative damage and cell apoptosis were evaluated. Transcriptome and co-immunoprecipitation analysis were used to screen the underlying molecular pathways. Meanwhile, primary cardiomyocytes were applied to confirm the beneficial effects of LUZP1 in depth.
RESULTS
LUZP1 was upregulated in DOX-injured hearts and cardiomyocytes. Cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated DOX-associated inflammation, oxidative damage, cell apoptosis and acute cardiac injury. Mechanistic studies revealed that LUZP1 ameliorated DOX-induced cardiotoxicity through activating 5'-AMP-activated protein kinase (AMPK) pathway, and AMPK deficiency abolished the cardioprotection of LUZP1. Further findings suggested that LUZP1 interacted with protein phosphatase 1 to activate AMPK pathway. Moreover, we determined that cardiac-specific LUZP1 overexpression could also attenuate DOX-associated chronic cardiac injury in mice.
CONCLUSION
LUZP1 attenuates DOX-induced inflammation, oxidative damage, cell apoptosis and ventricular impairment through regulating AMPK pathway, and gene therapy targeting LUZP1 may provide novel therapeutic approached to treat DOX-induced cardiotoxicity.
Topics: Mice; Animals; Cardiotoxicity; AMP-Activated Protein Kinases; Leucine Zippers; Doxorubicin; Myocytes, Cardiac; Oxidative Stress; Apoptosis; Heart Injuries; Inflammation; DNA-Binding Proteins
PubMed: 37354826
DOI: 10.1016/j.redox.2023.102780 -
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 -
Redox Biology Sep 2023Doxorubicin (DOX) is among the most widely employed antitumor agents, although its clinical applications have been largely hindered by severe cardiotoxicity. Earlier...
BACKGROUND
Doxorubicin (DOX) is among the most widely employed antitumor agents, although its clinical applications have been largely hindered by severe cardiotoxicity. Earlier studies described an essential role of mitochondrial injury in the pathogenesis of DOX cardiomyopathy. PHB2 (Prohibitin 2) is perceived as an essential regulator for mitochondrial dynamics and oxidative phosphorylation (OXPHOS) although its involvement in DOX cardiomyopathy remains elusive.
METHODS
To decipher the possible role of PHB2 in DOX cardiomyopathy, tamoxifen-induced cardiac-specific PHB2 conditional knockout mice were generated and subjected to DOX challenge. Cardiac function and mitochondrial profiles were examined. Screening of downstream mediators of PHB2 was performed using proteomic profiling and bioinformatic analysis, and was further verified using co-immunoprecipitation and pulldown assays.
RESULTS
Our data revealed significantly downregulated PHB2 expression in DOX-challenged mouse hearts. PHB2 mice were more susceptible to DOX cardiotoxicity compared with PHB2 mice, as evidenced by more pronounced cardiac atrophy, interstitial fibrosis and decrease in left ventricular ejection fraction and fractional shortening. Mechanistically, PHB2 deficiency resulted in the impairment of mitochondrial bioenergetics and oxidative phosphorylation in DOX cardiotoxicity. Proteomic profiling and interactome analyses revealed that PHB2 interacted with NDUFV2 (NADH-ubiquinone oxidoreductase core subunit V2), a key subunit of mitochondrial respiratory Complex I to mediate regulatory property of PHB2 on mitochondrial metabolism. PHB2 governed the expression of NDUFV2 by promoting its stabilization, while PHB2 deficiency significantly downregulated NDUFV2 in DOX-challenged hearts. Cardiac overexpression of PHB2 alleviated mitochondrial defects in DOX cardiomyopathy both in vivo and in vitro.
CONCLUSIONS
Our study defined a novel role for PHB2 in mitochondrial dynamics and energetic metabolism through interacting with NDUFV2 in DOX-challenged hearts. Forced overexpression of PHB2 may be considered a promising therapeutic approach for patients with DOX cardiomyopathy.
Topics: Mice; Animals; Cardiotoxicity; Electron Transport Complex I; Proteomics; Stroke Volume; Ventricular Function, Left; Cardiomyopathies; Doxorubicin; Apoptosis; Oxidative Stress
PubMed: 37451140
DOI: 10.1016/j.redox.2023.102812 -
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