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Nature Communications Mar 2024Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC...
Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.
Topics: Humans; Myeloid-Derived Suppressor Cells; Glutamine; Hematologic Neoplasms; Adenosine Triphosphate; Doxorubicin; Succinates
PubMed: 38555305
DOI: 10.1038/s41467-024-47096-9 -
Biochimica Et Biophysica Acta.... Aug 2023Cancer-associated fibroblasts (CAFs) are the predominant stromal cells in the microenvironment and play important roles in tumor progression, including chemoresistance....
Cancer-associated fibroblasts (CAFs) are the predominant stromal cells in the microenvironment and play important roles in tumor progression, including chemoresistance. However, the response of CAFs to chemotherapeutics and their effects on chemotherapeutic outcomes are largely unknown. In this study, we showed that epirubicin (EPI) treatment triggered ROS which initiated autophagy in CAFs, TCF12 inhibited autophagy flux and further promoted exosome secretion. Inhibition of EPI-induced reactive oxygen species (ROS) production with N-acetyl-L-cysteine (NAC) or suppression of autophagic initiation with short interfering RNA (siRNA) against ATG5 blunted exosome release from CAFs. Furthermore, exosome secreted from EPI-treated CAFs not only prevented ROS accumulation in CAFs but also upregulated the CXCR4 and c-Myc protein levels in recipient ER+ breast cancer cells, thus promoting EPI resistance of tumor cells. Together, the current study provides novel insights into the role of stressed CAFs in promoting tumor chemoresistance and reveal a new function of TCF12 in regulating autophagy impairment and exosome release.
Topics: Humans; Female; Cancer-Associated Fibroblasts; Breast Neoplasms; Epirubicin; Reactive Oxygen Species; Drug Resistance, Neoplasm; Fibroblasts; Exosomes; Tumor Microenvironment; Basic Helix-Loop-Helix Transcription Factors
PubMed: 37137433
DOI: 10.1016/j.bbadis.2023.166727 -
Journal of Cellular and Molecular... Sep 2023Considering the unfavourable response of breast cancer (BC) to treatment, we assessed the therapeutic potential hesperidin in mice bearing 4T1 BC tumours. Anti-tumour...
Considering the unfavourable response of breast cancer (BC) to treatment, we assessed the therapeutic potential hesperidin in mice bearing 4T1 BC tumours. Anti-tumour effects were assessed by measuring pathologic complete response (pCR), survival analysis, immunohistochemistry for E-cadherin, VEGF, MMP9, MMP2 and Ki-67, serum measurement of IFNγ and IL-4, and gene expression analysis of CD105, VEGFa, VEGFR2 and COX2. Survival of tumour-bearing mice was the highest in mice receiving a combination of hesperidin and doxorubicin (Dox) (80%) compared to the normal saline (43%), hesperidin 5 (54%), 10 (55.5%), 10 (60.5%) and 40 (66%) mg/kg, and 10 mg/kg Dox-treated (73%) groups (p < 0.0001 for all). Compared to the normal saline group, there was a significant elevation in IFNγ level in the animals receiving 20 (p = 0.0026) and 40 (p < 0.001) mg/kg hesperidin, 10 mg/kg Dox (p < 0.001), and combined hesperidin (20 mg/kg) and Dox (10 mg/kg) (p < 0.001). A significant reduction in the gene expression of CD 105 (p = 0.0106), VEGFa (p < 0.0001), VEGFR2 (p < 0.0001), and Cox2 (p = 0.034) and a significant higher pCR score (p = 0.006) were noticed in mice treated with 10 mg/kg Dox + 20 mg/kg hesperidin compared to those treated with 10 mg/kg Dox alone. Immunohistochemical staining showed significant reductions in Ki-67 (p < 0.001) and VEGF (p < 0.001) and a significant elevation in E-cadherin (p = 0.005) in the 10 mg/kg Dox + 20 mg/kg treatment group than in 10 mg/kg Dox alone group. Hesperidin can be considered as a potentially suitable anti-cancer agent for BC that can synergize with other chemotherapeutics.
Topics: Mice; Animals; Hesperidin; Mice, Inbred BALB C; Cyclooxygenase 2; Ki-67 Antigen; Vascular Endothelial Growth Factor A; Saline Solution; Doxorubicin; Cadherins; Cell Line, Tumor; Neoplasms
PubMed: 37581480
DOI: 10.1111/jcmm.17902 -
International Journal of Biological... 2023Anthracyclines are a class of conventionally and routinely used first-line chemotherapy drugs for cancer treatment. In addition to the direct cytotoxic effects,...
Anthracyclines are a class of conventionally and routinely used first-line chemotherapy drugs for cancer treatment. In addition to the direct cytotoxic effects, increasing evidence indicates that the efficacy of the drugs also depends on immunomodulatory effects with unknown mechanisms. Galectin-9 (Gal-9), a member of the β-galactoside-binding protein family, has been demonstrated to induce T-cell death and promote immunosuppression in the tumor microenvironment. Here, we asked whether anthracycline-mediated immunomodulatory activity might be related to Gal-9. We found that combining doxorubicin with anti-Gal-9 therapy significantly inhibited tumor growth and prolonged overall survival in immune-competent syngeneic mouse models. Moreover, Gal-9 expression was increased in response to doxorubicin in various human and murine cancer cell lines. Mechanistically, doxorubicin induced tumoral Gal-9 by activating the STING/interferon β pathway. Clinically, Gal-9 and p-STING levels were elevated in the tumor tissues of breast cancer patients treated with anthracyclines. Our study demonstrates Gal-9 upregulation in response to anthracyclines as a novel mechanism mediating immune escape and suggests targeting Gal-9 in combination with anthracyclines as a promising therapeutic strategy for cancer treatment.
Topics: Humans; Mice; Animals; Anthracyclines; Galectins; Neoplasms; Antineoplastic Agents; Antibiotics, Antineoplastic; Doxorubicin; Tumor Microenvironment
PubMed: 37781042
DOI: 10.7150/ijbs.84108 -
PloS One 2023Although doxorubicin (DOX) is an efficient chemotherapeutic drug for human tumors, severe cardiotoxicity restricts its clinical use. Cinnamaldehyde (CA), a bioactive...
Although doxorubicin (DOX) is an efficient chemotherapeutic drug for human tumors, severe cardiotoxicity restricts its clinical use. Cinnamaldehyde (CA), a bioactive component isolated from Cinnamonum cassia, possesses potent anti-oxidative and anti-apoptotic potentials. The major aim of this study was to evaluate the protective role of CA against DOX-induced cardiotoxicity. To this end, cardiomyocyte injury models were developed using DOX-treated H9c2 cells and DOX-treated rats, respectively. Herein, we found that CA treatment increased cardiomyocyte viability and attenuated DOX-induced cardiomyocyte death in vitro. CA further protected rats against DOX-induced cardiotoxicity, as indicated by elevated creatine kinase (CK) and lactate dehydrogenase (LDH) levels, myocardium injury, and myocardial fibrosis. CA alleviated DOX-induced myocardial oxidative stress by regulating reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels. Mechanistically, CA markedly accelerated nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2) and increased heme oxygenase-1 (HO-1) expression. Consequently, CA decreased DOX-induced cardiomyocyte ferroptosis, while Erastin (a ferroptosis agonist) treatment destroyed the effect of CA on increasing cardiomyocyte viability. Taken together, the current results demonstrate that CA alleviates DOX-induced cardiotoxicity, providing a promising opportunity to increase the clinical application of DOX.
Topics: Rats; Humans; Animals; Myocytes, Cardiac; Cardiotoxicity; Ferroptosis; Oxidative Stress; Doxorubicin; Glutathione; Apoptosis
PubMed: 37824478
DOI: 10.1371/journal.pone.0292124 -
Drug Delivery Dec 2023Doxorubicin (DOX), a commonly used anti-cancer drug, is limited by its cardiotoxicity and multidrug resistance (MDR) of tumor cells. Epigallocatechin gallate (EGCG), a...
Doxorubicin (DOX), a commonly used anti-cancer drug, is limited by its cardiotoxicity and multidrug resistance (MDR) of tumor cells. Epigallocatechin gallate (EGCG), a natural antioxidant component, can effectively reduce the cardiotoxicity of DOX. Meanwhile, EGCG can inhibit the expression of P-glycoprotein (P-gp) and reverse the MDR of tumor cells. In this study, DOX is connected with low molecular weight polyethyleneimine (PEI) via hydrazone bond to get the pH-sensitive PEI-DOX, which is then combined with EGCG to prevent the cardiotoxicity of DOX and reverse the MDR of cancer cells. In addition, folic acid (FA) modified polyethylene glycol (PEG) (PEG-FA) is added to get the targeted system PEI-DOX/EGCG/FA. The MDR reversal and targeting ability of PEI-DOX/EGCG/FA is performed by cytotoxicity and anti-tumor activity on multidrug resistant MCF-7 cells (MCF-7/ADR). Additionally, we investigate the anti-drug resistant mechanism by Western Blot. The ability of EGCG to reduce DOX cardiotoxicity is confirmed by cardiotoxicity assay. In conclusion, PEI-DOX/EGCG/FA can inhibit the expression of P-gp and reverse the MDR in tumor cells. It also shows the ability of remove oxygen free radicals effectively to prevent the cardiotoxicity of DOX.
Topics: Humans; Female; Breast Neoplasms; Cardiotoxicity; Drug Resistance, Neoplasm; Doxorubicin; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; MCF-7 Cells; Polyethylene Glycols
PubMed: 36919676
DOI: 10.1080/10717544.2023.2189118 -
Journal of Nanobiotechnology Aug 2023The excellent physicochemical and biomedical properties make silk fibroin (SF) suitable for the development of biomedical materials. In this research, the silk fibroin...
BACKGROUND
The excellent physicochemical and biomedical properties make silk fibroin (SF) suitable for the development of biomedical materials. In this research, the silk fibroin microspheres (SFMS) were customized in two size ranges, and then carried gold nanoparticles or doxorubicin to evaluate the performance of drug loading and releasing. Embolization efficiency was evaluated in rat caudal artery and rabbit auricular artery, and the in vivo distribution of iodinated SFMS (I/I-SFMS) after embolization of rat hepatic artery was dynamically recorded by SPECT. Transhepatic arterial radioembolization (TARE) with I-SFMS was performed on rat models with liver cancer. The whole procedure of selective internal radiation was recorded with SPECT/CT, and the therapeutic effects were evaluated with F-FDG PET/CT. Lastly, the enzymatic degradation was recorded and followed with the evaluation of particle size on clearance of sub-micron silk fibroin.
RESULTS
SFMS were of smooth surface and regular shape with pervasive pores on the surface and inside the microspheres, and of suitable size range for TAE. Drug-loading functionalized SFMS with chemotherapy or radio-sensitization, and the enhanced therapeutic effects were proved in treating HUH-7 cells as lasting doxorubicin release or more lethal radiation. For artery embolization, SFMS effectively blocked the blood supply; when I-SFMS serving as the embolic agent, the good labeling stability and embolization performance guaranteed the favorable therapeutic effects in treating in situ liver tumor. At the 5th day post TARE with 37 MBq/3 mg I-SFMS per mice, tumor activity was quickly inhibited to a comparable glucose metabolism level with surrounding normal liver. More importantly, for the fragments of biodegradable SFMS, smaller sized SF (< 800 nm) metabolized in gastrointestinal tract and excreted by the urinary system, while SF (> 800 nm) entered the liver within 72 h for further metabolism.
CONCLUSION
The feasibility of SFMS as degradable TARE agent for liver cancer was primarily proved as providing multiple therapeutic potentials.
Topics: Animals; Mice; Rabbits; Rats; Fibroins; Gold; Positron Emission Tomography Computed Tomography; Metal Nanoparticles; Arteries; Doxorubicin
PubMed: 37598140
DOI: 10.1186/s12951-023-02032-9 -
Cell Death & Disease Aug 2023In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies...
In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies have shown that high levels of Δ40p53 are associated with worse disease-free survival and disruption of p53-induced DNA damage response in breast cancers. Here, we further investigated the in vitro and in vivo implications of Δ40p53 expression in breast cancer. We have shown that genes associated with cell differentiation are downregulated while those associated with stem cell regulation are upregulated in invasive ductal carcinomas expressing high levels of Δ40p53. In contrast to p53, endogenous ∆40p53 co-localised with the stem cell markers Sox2, Oct4, and Nanog in MCF-7 and ZR75-1 cell lines. ∆40p53 and Sox2 co-localisation was also detected in breast cancer specimens. Further, in cells expressing a high ∆40p53:p53 ratio, increased expression of stem cell markers, greater mammosphere and colony formation capacities, and downregulation of miR-145 and miR-200 (p53-target microRNAs that repress stemness) were observed compared to the control subline. In vivo, a high ∆40p53:p53 ratio led to increased tumour growth, Ki67 and Sox2 expression, and blood microvessel areas in the vehicle-treated mice. High expression of ∆40p53 also reduced tumour sensitivity to doxorubicin compared to control tumours. Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting Δ40p53 in tumours that have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin.
Topics: Animals; Mice; Tumor Suppressor Protein p53; Cell Line, Tumor; Doxorubicin; MicroRNAs; Protein Isoforms; Neoplasms
PubMed: 37553320
DOI: 10.1038/s41419-023-06031-4 -
European Review For Medical and... Oct 2023OBJECTIVE: The anticancer drug doxorubicin (DOX) is effective but is associated with complications such as hypothyroidism and cardiotoxicity. Pioglitazone (PIO), which...
UNLABELLED
OBJECTIVE: The anticancer drug doxorubicin (DOX) is effective but is associated with complications such as hypothyroidism and cardiotoxicity. Pioglitazone (PIO), which is used to treat diabetes mellitus, has shown potential for treating hypothyroidism and cardiac dysfunction. Therefore, this study explores whether PIO can also ameliorate DOX-induced hypothyroidism and cardiotoxicity. MATERIALS AND METHODS: Forty female Wistar rats were separated into control and three treated groups (DOX, PIO, and DOX+PIO), and their blood samples were examined for the thyroid hormones, including thyroid-stimulating hormone (TSH), thyroxine in total and free forms (T4 and FT4, respectively), and triiodothyronine in total and free forms (T3 and FT3, respectively), and the cardiotoxicity biomarkers [troponin I, creatine kinase (CK), and creatine kinase-myocardial band (CK-MB)]. RESULTS: The control and PIO groups did not exhibit significant alterations in any of the examined hormones and markers. In contrast, in the DOX group, T4, FT4, T3, and FT3 levels decreased significantly, whereas troponin I, CK, and CK-MB levels increased significantly, but no significant changes were detected in TSH levels. PIO co-treatment ameliorated these effects of DOX significantly in FT4, FT3, and troponin I. CONCLUSIONS: PIO may provide protection against hypothyroidism and cardiotoxicity caused by DOX treatment, by significant reversal of FT4, FT3, and troponin I levels.
GRAPHICAL ABSTRACT
https://www.europeanreview.org/wp/wp-content/uploads/Graphical-abstract1.jpg.
Topics: Female; Rats; Animals; Pioglitazone; Cardiotoxicity; Troponin I; Rats, Wistar; Hypothyroidism; Thyroxine; Doxorubicin; Thyrotropin; Creatine Kinase, MB Form; Creatine Kinase
PubMed: 37843360
DOI: 10.26355/eurrev_202310_33966 -
Biomedicine & Pharmacotherapy =... Apr 2024Diffuse large B-cell lymphoma (DLBCL), a heterogeneous lymphoid malignancy, poses a significant threat to human health. The standard therapeutic regimen for patients... (Review)
Review
Diffuse large B-cell lymphoma (DLBCL), a heterogeneous lymphoid malignancy, poses a significant threat to human health. The standard therapeutic regimen for patients with DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), with a typical cure rate of 50-70%. However, some patients either relapse after complete remission (CR) or exhibit resistance to R-CHOP treatment. Therefore, novel therapeutic approaches are imperative for managing high-risk or refractory DLBCL. Ferroptosis is driven by iron-dependent phospholipid peroxidation, a process that relies on the transition metal iron, reactive oxygen species (ROS), and phospholipids containing polyunsaturated fatty acids-containing phospholipids (PUFA-PLs). Research indicates that ferroptosis is implicated in various carcinogenic and anticancer pathways. Several hematological disorders exhibit heightened sensitivity to cell death induced by ferroptosis. DLBCL cells, in particular, demonstrate an increased demand for iron and an upregulation in the expression of fatty acid synthase. Additionally, there exists a correlation between ferroptosis-associated genes and the prognosis of DLBCL. Therefore, ferroptosis may be a promising novel target for DLBCL therapy. In this review, we elucidate ferroptosis mechanisms, its role in DLBCL, and the potential therapeutic targets in DLBCL. This review offers novel insights into the application of ferroptosis in treatment strategies for DLBCL.
Topics: Humans; Ferroptosis; Neoplasm Recurrence, Local; Rituximab; Vincristine; Cyclophosphamide; Prednisone; Doxorubicin; Lymphoma, Large B-Cell, Diffuse; Iron; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 38492438
DOI: 10.1016/j.biopha.2024.116386