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Lipids in Health and Disease Oct 2023Ceramide, a bioactive signaling sphingolipid, has long been implicated in cancer. Members of the ceramide synthase (CerS) family determine the acyl chain lengths of...
BACKGROUND
Ceramide, a bioactive signaling sphingolipid, has long been implicated in cancer. Members of the ceramide synthase (CerS) family determine the acyl chain lengths of ceramides, with ceramide synthase 4 (CerS4) primarily generating C18-C20-ceramide. Although CerS4 is known to be overexpressed in breast cancer, its role in breast cancer pathogenesis is not well established.
METHODS
To investigate the role of CerS4 in breast cancer, public datasets, including The Cancer Genome Atlas (TCGA) and two Gene Expression Omnibus (GEO) datasets (GSE115577 and GSE96058) were analyzed. Furthermore, MCF-7 cells stably overexpressing CerS4 (MCF-7/CerS4) as a model for luminal subtype A (LumA) breast cancer were produced, and doxorubicin (also known as Adriamycin [AD])-resistant MCF-7/ADR cells were generated after prolonged treatment of MCF-7 cells with doxorubicin. Kaplan-Meier survival analysis assessed the clinical significance of CERS4 expression, while Student's t-tests or Analysis of Variance (ANOVA) compared gene expression and cell viability in different MCF-7 cell lines.
RESULTS
Analysis of the public datasets revealed elevated CERS4 expression in breast cancer, especially in the most common breast cancer subtype, LumA. Persistent CerS4 overexpression in MCF-7 cells activated multiple cancer-associated pathways, including pathways involving sterol regulatory element-binding protein, nuclear factor kappa B (NF-κB), Akt/mammalian target of rapamycin (mTOR), and β-catenin. Furthermore, MCF-7/CerS4 cells acquired doxorubicin, paclitaxel, and tamoxifen resistance, with concomitant upregulation of ATP-binding cassette (ABC) transporter genes, such as ABCB1, ABCC1, ABCC2, ABCC4, and ABCG2. MCF-7/CerS4 cells were characterized by increased cell migration and epithelial-mesenchymal transition (EMT). Finally, CERS4 knockdown in doxorubicin-resistant MCF-7/ADR cells resulted in reduced activation of cancer-associated pathways (NF-κB, Akt/mTOR, β-catenin, and EMT) and diminished chemoresistance, accompanied by ABCB1 and ABCC1 downregulation.
CONCLUSIONS
Chronic CerS4 overexpression may exert oncogenic effects in breast cancer via alterations in signaling, EMT, and chemoresistance. Therefore, CerS4 may represent an attractive target for anticancer therapy, especially in LumA breast cancer.
Topics: Female; Humans; ATP-Binding Cassette Transporters; beta Catenin; Breast Neoplasms; Doxorubicin; Drug Resistance, Neoplasm; NF-kappa B; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Sphingosine N-Acyltransferase; MCF-7 Cells
PubMed: 37885013
DOI: 10.1186/s12944-023-01930-z -
Journal of Nanobiotechnology Apr 2024Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is...
Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-β-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.
Topics: Humans; Mice; Animals; Myocytes, Cardiac; Induced Pluripotent Stem Cells; MicroRNAs; Cardiomyopathies; Signal Transduction; Doxorubicin
PubMed: 38643173
DOI: 10.1186/s12951-024-02421-8 -
International Journal of Molecular... Aug 2023Unlike genomic alterations, gene expression profiles have not been widely used to refine cancer therapies. We analyzed transcriptional changes in acute myeloid leukemia...
Unlike genomic alterations, gene expression profiles have not been widely used to refine cancer therapies. We analyzed transcriptional changes in acute myeloid leukemia (AML) cell lines in response to standard first-line AML drugs cytarabine and daunorubicin by means of RNA sequencing. Those changes were highly cell- and treatment-specific. By comparing the changes unique to treatment-sensitive and treatment-resistant AML cells, we enriched for treatment-relevant genes. Those genes were associated with drug response-specific pathways, including calcium ion-dependent exocytosis and chromatin remodeling. Pharmacological mimicking of those changes using EGFR and MEK inhibitors enhanced the response to daunorubicin with minimum standalone cytotoxicity. The synergistic response was observed even in the cell lines beyond those used for the discovery, including a primary AML sample. Additionally, publicly available cytotoxicity data confirmed the synergistic effect of EGFR inhibitors in combination with daunorubicin in all 60 investigated cancer cell lines. In conclusion, we demonstrate the utility of treatment-evoked gene expression changes to formulate rational drug combinations. This approach could improve the standard AML therapy, especially in older patients.
Topics: Humans; Aged; Leukemia, Myeloid, Acute; Daunorubicin; Cell Line; Chromatin Assembly and Disassembly; ErbB Receptors
PubMed: 37629110
DOI: 10.3390/ijms241612926 -
Journal of Veterinary Internal Medicine 2023This study was performed to determine the ability to escalate drug doses in a 15-week CHOP protocol in dogs with multicentric lymphoma.
BACKGROUND
This study was performed to determine the ability to escalate drug doses in a 15-week CHOP protocol in dogs with multicentric lymphoma.
HYPOTHESIS
We hypothesized that at least 50% of dogs could successfully be escalated in at least 1 drug. Secondary aims were to establish objective response rate (ORR), progression-free interval (PFI), and overall survival time (OST).
ANIMALS
Thirty dogs with newly diagnosed multicentric lymphoma were prospectively treated with a 15-week CHOP protocol.
METHODS
This was a prospective cohort study. Drug doses that did not cause dose-limiting adverse effects (AEs) were increased using a standardized escalation protocol. AEs and response were assessed using VCOG criteria. Serial blood samples were collected after the first dose of each drug for pharmacokinetic analysis.
RESULTS
Of the 23 dogs with the opportunity to dose escalate, at least 1 drug was successfully escalated in 18 (78%). Vincristine was successfully escalated to 0.8 mg/m or higher in 11 dogs, cyclophosphamide to 300 mg/m or higher in 16 dogs, and doxorubicin to 35 mg/m or 1.4 mg/kg or higher in 9 dogs. Three of the 23 dogs (13%) were hospitalized at least once because of drug-induced AEs. Neutropenia was the most common dose-limiting toxicosis for all drugs. Peak doxorubicin concentrations were significantly lower in dogs where doxorubicin was successfully escalated. The objective response rate was 100%. The median progression free interval was 171 days. The median overall survival time was 254 days.
CONCLUSIONS
Drugs in the CHOP protocol can often be escalated safely with manageable AEs.
Topics: Humans; Dogs; Animals; Prospective Studies; Lymphoma; Neutropenia; Doxorubicin; Dog Diseases
PubMed: 37787577
DOI: 10.1111/jvim.16875 -
Journal of Oleo Science Oct 2023In this study, we analyzed the properties of amphiphilic alkyldi(methoxy poly(ethylene glycol) (MePEG)350-lactate) phosphates based on ethyl lactate, the monomethyl...
In this study, we analyzed the properties of amphiphilic alkyldi(methoxy poly(ethylene glycol) (MePEG)350-lactate) phosphates based on ethyl lactate, the monomethyl ether of poly(ethylene glycol)350, and alkyldichloro phosphates. Interestingly, these triesters combine two biodegradable bonds, -P(O)-O-C and -C(O)-O-C-, and include hydrophilic (MePEG350-lactate) and hydrophobic (R-aliphatic chain of alcohols) moieties. The properties of these esters resemble those of phospholipids. After being placed in an aqueous solution, they self-assembled. We also determined the effects of ester composition on micelle formation, stability, and size using dynamic light scattering. Solubilization tests using Sudan III or doxorubicin hydrochloride (Dox·HCl) revealed that they could be incorporated into the hydrophobic cores of dodecyl di(MePEG350-lactate) phosphate and hexadecyl di(MePEG350-lactate) phosphate. Notably, dodecyl di(MePEG350-lactate) phosphate was stable for five days, whereas hexadecyl di(MePEG350-lactate) phosphate was stable for seven days in phosphate-buffered saline. Moreover, Dox·HCl release rates from the micelles were approximately 30-40, 70-80, and 90-100% after 1, 5, and 28 d, respectively.
Topics: Micelles; Polyethylene Glycols; Doxorubicin; Phosphates; Lactates; Drug Carriers
PubMed: 37704442
DOI: 10.5650/jos.ess23108 -
ELife Apr 2024Chemotherapy is a widely used treatment for a variety of solid and hematological malignancies. Despite its success in improving the survival rate of cancer patients,...
Chemotherapy is a widely used treatment for a variety of solid and hematological malignancies. Despite its success in improving the survival rate of cancer patients, chemotherapy causes significant toxicity to multiple organs, including the skeleton, but the underlying mechanisms have yet to be elucidated. Using tumor-free mouse models, which are commonly used to assess direct off-target effects of anti-neoplastic therapies, we found that doxorubicin caused massive bone loss in wild-type mice, a phenotype associated with increased number of osteoclasts, leukopenia, elevated serum levels of danger-associated molecular patterns (DAMPs; e.g. cell-free DNA and ATP) and cytokines (e.g. IL-1β and IL-18). Accordingly, doxorubicin activated the absent in melanoma (AIM2) and NLR family pyrin domain containing 3 (NLRP3) inflammasomes in macrophages and neutrophils, causing inflammatory cell death pyroptosis and NETosis, which correlated with its leukopenic effects. Moreover, the effects of this chemotherapeutic agent on cytokine secretion, cell demise, and bone loss were attenuated to various extent in conditions of AIM2 and/or NLRP3 insufficiency. Thus, we found that inflammasomes are key players in bone loss caused by doxorubicin, a finding that may inspire the development of a tailored adjuvant therapy that preserves the quality of this tissue in patients treated with this class of drugs.
Topics: Humans; Animals; Mice; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Alarmins; Doxorubicin; Inflammation; Melanoma
PubMed: 38602733
DOI: 10.7554/eLife.92885 -
Journal of Cancer Research and... Dec 2023To investigate the drug loading and release rate of epirubicin-loaded thermosensitive liquid embolic agents in vitro.
OBJECTIVE
To investigate the drug loading and release rate of epirubicin-loaded thermosensitive liquid embolic agents in vitro.
MATERIALS AND METHODS
The drug loading and stability of epirubicin-loaded thermosensitive liquid embolic agents with or without iopromide were determined by high-performance liquid chromatography, and the same method was used to determine the drug release rate of thermosensitive liquid embolic agents at different time points.
RESULTS
For epirubicin-loaded thermosensitive liquid embolic agents without iopromide, the average drug loading after filtration by membrane was (0.78 ± 0.02) mg and the drug loading rate was (16.1 ± 0.35)%, while the average drug loading without membrane was (0.73 ± 0.06) mg and the drug loading rate was (15.07 ± 1.17)%. After adding iopromide, the drug loading capacity was measured from 0 h-24 h solution and the drug loading was calculated indirectly and conclude that the drug loading capacity of thermosensitive liquid embolic agents decreased or disappeared. The sustained release rate of epirubicin from 0 to 48 hours was 42.65% in 48 hours.
CONCLUSION
Epirubicin can be successfully loaded into the thermosensitive liquid embolic agents with good stability and sustained release. After adding iopromide, the drug loading capacity of thermosensitive liquid embolic agents decreased or disappeared.
Topics: Humans; Epirubicin; Delayed-Action Preparations; Iohexol; Drug Liberation
PubMed: 38156927
DOI: 10.4103/jcrt.jcrt_334_23 -
Pharmacological Research Nov 2023Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However,...
Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers.
Topics: Humans; Pharmaceutical Preparations; Neoplasms; Cell Death; Lysosomes; Mitochondria; Erythrocytes; Doxorubicin
PubMed: 37797662
DOI: 10.1016/j.phrs.2023.106945 -
CPT: Pharmacometrics & Systems... Dec 2023Limited information is available concerning infant exposure and safety when breastfed by mothers receiving chemotherapy. Whereas defining distribution to breast milk is...
Limited information is available concerning infant exposure and safety when breastfed by mothers receiving chemotherapy. Whereas defining distribution to breast milk is important to infer drug exposure, infant pharmacokinetics also determine to what extent the infant will be exposed to potential toxic effects. We aimed to assess the impact of chemotherapy containing breast milk on infants by predicting systemic and local (intestinal) exposure of paclitaxel and doxorubicin in infants through breast milk using a physiologically-based pharmacokinetic (PBPK) approach. Whole-body PBPK models of i.v. paclitaxel and doxorubicin were extended from the literature, with an oral absorption component to enable predictions in infants receiving paclitaxel or doxorubicin-containing breast milk. For safety considerations, worst-case scenarios were explored. Finally, paclitaxel and doxorubicin exposures in plasma and intestinal tissue of infants following feeding of breast milk from paclitaxel- or doxorubicin-treated mothers were simulated and breast milk discarding strategies were evaluated. The upper 95th percentile of the predicted peak concentrations in peripheral venous blood were 3.48 and 0.74 nM (0.4%-1.7% and 0.1%-1.8% of on-treatment) for paclitaxel and doxorubicin, respectively. Intestinal exposure reached peak concentrations of 1.0 and 140 μM for paclitaxel and doxorubicin, respectively. Discarding breast milk for the first 3 days after maternal chemotherapy administration reduced systemic and tissue exposures even further, to over 90% and 80% for paclitaxel and doxorubicin, respectively. PBPK simulations of chemotherapy exposure in infants after breastfeeding with chemotherapy containing breast milk suggest that particularly local gastrointestinal adverse events should be monitored, whereas systemic adverse events are not expected.
Topics: Infant; Female; Humans; Milk, Human; Paclitaxel; Breast Feeding; Doxorubicin; Mothers
PubMed: 37798909
DOI: 10.1002/psp4.13043 -
Biomedicine & Pharmacotherapy =... Sep 2023The response of advanced hepatocellular carcinoma (HCC) to pharmacological treatments is unsatisfactory and heterogeneous. Inactivation of tumor suppressor genes (TSGs)...
The response of advanced hepatocellular carcinoma (HCC) to pharmacological treatments is unsatisfactory and heterogeneous. Inactivation of tumor suppressor genes (TSGs) by genetic and epigenetic events is frequent in HCC. This study aimed at investigating the impact of frequently altered TSGs on HCC chemoresistance. TSG alterations were screened by in silico analysis of TCGA-LIHC database, and their relationship with survival was investigated. These TSGs were silenced in HCC-derived cell lines using CRISPR/Cas9. TLDA was used to determine the expression of a panel of 94 genes involved in the resistome. Drug sensitivity, cell proliferation, colony formation and cell migration were assessed. The in silico study revealed the down-regulation of frequently inactivated TSGs in HCC (ARID1A, PTEN, CDH1, and the target of p53, CDKN1A). The presence of TP53 and ARID1A variants and the low expression of PTEN and CDH1 correlated with a worse prognosis of HCC patients. In PLC/PRF/5 cells, ARID1A knockout (ARID1A) induced increased sensitivity to cisplatin, doxorubicin, and cabozantinib, without affecting other characteristics of malignancy. PTEN and E-Cad showed minimal changes in malignancy, resistome, and drug response. In p53 HepG2 cells, enhanced malignant properties and higher resistance to cisplatin, doxorubicin, sorafenib, and regorafenib were found. This was associated with changes in the resistome. In conclusion, the altered expression and function of several TSGs are involved in the heterogeneity of HCC chemoresistance and other features of malignancy, contributing to the poor prognosis of these patients. Individual identification of pharmacological vulnerabilities is required to select the most appropriate treatment for each patient.
Topics: Humans; Carcinoma, Hepatocellular; Tumor Suppressor Protein p53; Liver Neoplasms; Cisplatin; Cell Line, Tumor; Doxorubicin; Genes, Tumor Suppressor; Drug Resistance, Multiple; Phenotype
PubMed: 37499450
DOI: 10.1016/j.biopha.2023.115209