-
Histochemistry and Cell Biology Jun 2024DNA damage is one of the most important effects induced by chemical agents. We report a comparative analysis of DNA fragmentation on three different cell lines using...
DNA damage is one of the most important effects induced by chemical agents. We report a comparative analysis of DNA fragmentation on three different cell lines using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, generally applied to detect apoptosis. Our approach combines cytogenetic techniques and investigation in detached cellular structures, recovered from the culture medium with the aim to compare the DNA fragmentation of three different cell line even beyond the cells adherent to substrate. Consequently, we detect any fragmentation points on single chromosomes, whole nuclei and other cellular structures. Cells were exposed to resveratrol (RSV) and doxorubicin (Doxo), in single and combined treatments. Control and treated astrocytes showed DNA damage in condensed nuclei and detached structures. Caco-2 cells showed fragmented DNA only after Doxo-treatment, while controls showed fragmented chromosomes, indicating DNA damage in replicating cells. MDA-MB-231 cells showed nuclear condensation and DNA fragmentation above all after RSV-treatment and related to detached structures. This model proved to perform a grading of genomic instability (GI). Astrocytes show a hybrid level of GI. Caco-2 cells showed fragmented metaphase chromosomes, proving that the DNA damage was transmitted to the daughter cells probably due to an absence of DNA repair mechanisms. Instead, MDA-MB-231 cells showed few or no fragmented metaphase, suggesting a probable activation of DNA repair mechanisms. By applying this alternative approach of TUNEL test, we obtained data that can more specifically characterize DNA fragmentation for a suitable application in various fields.
PubMed: 38940846
DOI: 10.1007/s00418-024-02306-9 -
Biomaterials Science Jun 2024PEGylation is currently used for the synthesis of stealth liposomes and to enhance the pharmacokinetic and biopharmaceutical properties of payloads. PEGylated dendron...
PEGylation is currently used for the synthesis of stealth liposomes and to enhance the pharmacokinetic and biopharmaceutical properties of payloads. PEGylated dendron phospholipids can decrease the detachment of polyethylene glycol (PEG) from the liposomal surface owing to an increased hydrophobic anchoring effect on the phospholipid bilayer of liposomes and thus generating super stealth liposomes that are suitable for the systemic delivery of anticancer drugs. Herein, doxorubicin hydrochloride-loaded super stealth liposomes were studied for the treatment of breast cancer lung metastasis in an animal model. The results demonstrated that the super stealth liposomes had suitable physicochemical properties for administration and could significantly increase the efficacy of doxorubicin in breast cancer lung metastasis tumor-bearing mice compared to the free drug. The super stealth liposomes also increased doxorubicin accumulation inside the tumor tissue. The permanence of PEG on the surface of the super stealth liposomes favored the formation of a depot of therapeutic nanocarriers inside the tumor tissue by improving their permanence after stopping treatment. The doxorubicin-loaded super stealth liposomes increased the survival of the mouse tumor model. These promising results demonstrate that the doxorubicin-loaded super stealth liposomes could be an effective nanomedicine to treat metastatic breast cancer.
PubMed: 38940612
DOI: 10.1039/d4bm00478g -
Future Oncology (London, England) Jun 2024A consensus regarding subsequent therapeutic strategies for patients with platinum- and poly (ADP-ribose) polymerase inhibitor (PARPi)-resistant ovarian cancer is...
A consensus regarding subsequent therapeutic strategies for patients with platinum- and poly (ADP-ribose) polymerase inhibitor (PARPi)-resistant ovarian cancer is lacking. These patients typically receive non-platinum-based chemotherapy; however, survival outcomes remain poor. Compared with chemotherapy alone, combination therapy with novel target agents can provide additional benefits to these patients. Oregovomab, an investigational murine monoclonal antibody against CA-125, has shown promising efficacy in a phase II study in patients with recurrent ovarian cancer. Herein, we described the rationale and design of OPERA/KGOG 3065/APGOT-OV6, a multicenter, investigator-initiated, two-cohort, single-arm phase II trial, aimed at examining the efficacy of oregovomab plus non-platinum-based chemotherapy in patients with PARPi/platinum-resistant ovarian cancer. The primary end point was the objective response rate, according to RECIST 1.1. NCT05407584 (ClinicalTrials.gov).
PubMed: 38940373
DOI: 10.1080/14796694.2024.2357533 -
Molecular Cancer Therapeutics Jun 2024Sarcomas are a heterogenous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases makes treatment challenging,...
BACKGROUND/INTRODUCTION
Sarcomas are a heterogenous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases makes treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which lead to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher, toxic doses of chemotherapy. Here, we tested the mechanotherapeutic ketotifen combined with either pegylated-liposomal doxorubicin (PLD) or pegylated-liposomal co-encapsulated alendronate-doxorubicin (PLAD) plus anti-PD-1 antibody in mouse models of fibrosarcoma and osteosarcoma.
RESULTS
We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave-elastography (SWE) and contrast-enhanced-ultrasound (CEUS) respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. An additional observation was a trend to improved antitumor response when nano-chemotherapy is given alongside anti-PD1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy, increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper-cell and decreased the number of regulatory-T-cells. In addition, the combination also altered the polarization of tumor associated macrophages, favouring the M1 immune-supportive phenotype over the M2 immuno-suppressive phenotype.
CONCLUSION
Collectively, our findings provide evidence that ketotifen-induced TME reprograming can improve the efficacy of nanomedicine-based chemoimmunotherapy in sarcomas.
PubMed: 38940284
DOI: 10.1158/1535-7163.MCT-23-0772 -
Biomeditsinskaia Khimiia Jun 2024The cytokine profile of primary coronary artery endothelial cells cultivated in the presence of doxorubicin (2 μg/ml and 6 μg/ml) was evaluated using enzyme-linked...
The cytokine profile of primary coronary artery endothelial cells cultivated in the presence of doxorubicin (2 μg/ml and 6 μg/ml) was evaluated using enzyme-linked immunosorbent assay and qPCR. Cultivation of cells in the presence of these concentrations of doxorubicin for 24 h, upregulated expression of the following genes: IL6 (by 2.30 and 2.66 times, respectively), IL1B (by 1.25 and 3.44 times), and CXCL8 (by 6.47 times and 6.42 times), MIF (2.34 and 2.28 times), CCL2 (4.22 and 3.98 times). Under these conditions the following genes were downregulated: IL10, IL1R2, TNF. Cultivation of cells in the presence of doxorubicin (2 μg/ml and 6 μg/ml) for 24 h also increased the secretion of IL-6.
Topics: Humans; Doxorubicin; Coronary Vessels; Endothelial Cells; Interleukin-6; Cells, Cultured; Interleukin-1beta; Cytokines; Gene Expression Regulation; Interleukin-8; Chemokine CCL2; Tumor Necrosis Factor-alpha; Interleukin-10
PubMed: 38940204
DOI: 10.18097/PBMC20247003156 -
Systematic Reviews Jun 2024Chemotherapy-related cardiotoxicity is a significant concern because it is a major cause of morbidity. This study aimed to provide in-depth information on the symptoms... (Review)
Review
BACKGROUND
Chemotherapy-related cardiotoxicity is a significant concern because it is a major cause of morbidity. This study aimed to provide in-depth information on the symptoms of chemotherapy-related cardiotoxicity (CRCT) by exploring literature that concurrently reports the types and symptoms of CRCT in patients with breast cancer.
METHODS
A scoping review was performed according to an a priori protocol using the Joanna Briggs Institute's guidelines. The participants were patients with breast cancer. The concept was the literature of specifically reported symptoms directly matched with CRCT and the literature, in English, from 2010, and the context was open. The search strategy included four keywords: "breast cancer," "chemotherapy," "cardiotoxicity," and "symptoms." All types of research designs were included; however, studies involving patients with other cancer types, animal subjects, and symptoms not directly related to CRCT were excluded. Data were extracted and presented including tables and figures.
RESULTS
A total of 29 articles were included in the study, consisting of 23 case reports, 4 retrospective studies, and 2 prospective studies. There were no restrictions on the participants' sex; however, all of them were women, except for one case report. The most used chemotherapy regimens were trastuzumab, capecitabine, and doxorubicin or epirubicin. The primary CRCT identified were myocardial dysfunction and heart failure, followed by coronary artery disease, pulmonary hypertension, and other conditions. Major tests used to diagnose CRCT include echocardiography, electrocardiography, serum cardiac enzymes, coronary angiography, computed tomography, and magnetic resonance imaging. In all case reports, CRCT was diagnosed through an incidental checkup according to the patient's symptom presentation; however, only 10 of these studies showed a baseline checkup before chemotherapy. The five most common CRCT symptoms were dyspnea, chest pain, peripheral edema, fatigue, and palpitations, which were assessed by patient-reported symptom presentation rather than using a symptom assessment tool. Dyspnea with trastuzumab treatment and chest pain with capecitabine treatment were particularly characteristic. The time for first symptom onset after chemotherapy ranged from 1 hour to 300 days, with anthracycline-based regimens requiring 3-55 days, trastuzumab requiring 60-300 days, and capecitabine requiring 1-7 days.
CONCLUSIONS
This scoping review allowed data mapping according to the study design and chemotherapy regimens. Cardiac assessments for CRCT diagnosis were performed according to the patient's symptoms. There were approximately five types of typical CRCT symptoms, and the timing of symptom occurrence varied. Therefore, developing and applying a CRCT-specific and user-friendly symptom assessment tool are expected to help healthcare providers and patients manage CRCT symptoms effectively.
Topics: Humans; Breast Neoplasms; Cardiotoxicity; Female; Antineoplastic Agents
PubMed: 38937811
DOI: 10.1186/s13643-024-02588-z -
BMC Chemistry Jun 2024In an attempt to develop potent anti-cancer agents, a new 1,3,4-substituted-thiadiazole derivatives (8b-g), starting from 4-substituted-thiazol-2-chloroacetamides...
In an attempt to develop potent anti-cancer agents, a new 1,3,4-substituted-thiadiazole derivatives (8b-g), starting from 4-substituted-thiazol-2-chloroacetamides (4b-g), were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the hepatocellular carcinoma (HEPG-2), human lung carcinoma (A549), human breast carcinoma (MCF-7) and pseudo-normal human embryonic liver (L02) cancer cell lines by an MTT assay. Among all synthesized compounds, compound 8d showed the potent anti-cancer activities with GI values of 2.98, 2.85 and 2.53 μM against MCF-7, A549 and HepG-2 cell lines respectively as compared to standard drug Doxorubicin. Furthermore, molecular modelling studies have spotlighted the anchoring role of 1,3,4-substituted-thiadiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. Therefore, these results can provide promising starting points for further development of best anti-cancer agents.
PubMed: 38937800
DOI: 10.1186/s13065-024-01196-1 -
Cellular Signalling Jun 2024Tumor-associated macrophages (TAMs) secrete cytokines, chemokines, and growth factors in the tumor microenvironment (TME) to support cancer progression. Higher TAM...
Tumor-associated macrophages (TAMs) secrete cytokines, chemokines, and growth factors in the tumor microenvironment (TME) to support cancer progression. Higher TAM infiltration in the breast TME is associated with a poor prognosis. Previous studies have demonstrated the role of macrophages in stimulating long-range intercellular bridges referred to as tunneling nanotubes (TNTs) in cancer cells. Intercellular communication between cancer cells via TNTs promotes cancer growth, invasion, metastasis, and therapy resistance. Given the important role of TNTs and macrophages in cancer, the role of macrophage-induced TNTs in chemotherapy drug doxorubicin resistance is not known. Furthermore, the mechanism of macrophage-mediated TNT formation is elusive. In this study, it is shown that the macrophage-conditioned medium (MΦCM) partially mimicked inflammatory TME, induced an EMT phenotype, and increased migration in MCF-7 breast cancer cells. Additionally, secreted proteins in MΦCM induced TNT formation in MCF-7 cells, which led to increased resistance to doxorubicin. Transcriptomic analysis of MΦCM-treated MCF-7 cells showed enrichment of the NF-κB and focal adhesion pathways, as well as upregulation of genes involved in EMT, extracellular remodeling, and actin cytoskeleton reorganization. Interestingly, inhibitors of PKC, Src, NF-κB, and p38 decreased macrophage-induced TNT formation in MCF-7 cells. These results reveal the novel role of PKC and Src in inducing TNT formation in cancer cells and suggest that inhibition of PKC and Src activity may likely contribute to reduced macrophage-breast cancer cell interaction and the potential therapeutic strategy of cancer.
PubMed: 38936787
DOI: 10.1016/j.cellsig.2024.111274 -
Acta Biomaterialia Jun 2024Triple-negative breast cancer (TNBC) is a relatively "cold" tumour with low immunogenicity compared to other tumour types. Especially, the immune checkpoint inhibitors...
Triple-negative breast cancer (TNBC) is a relatively "cold" tumour with low immunogenicity compared to other tumour types. Especially, the immune checkpoint inhibitors to treat metastatic TNBC only shows the modest immune response rates. Here, we used Chlorella vulgaris as a bioreactor to synthesize an efficient nanobomb (Bio-MnSe) aimed at eliciting systemic anti-tumour immune response. Despite possessing extremely low Mn content, Bio-MnSe effectively produced more ROS and activated stronger cGAS-STING signal pathway compared to pure Se nanoparticles and free Mn ions, promoting the infiltration of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) in tumour, effectively turning "cold" tumour into "hot" tumour, and achieving strong antitumour immunotherapy. Additionally, the use of αPD-L1 as an immune checkpoint antagonist further increased the anti-tumour immune response of Bio-MnSe, resulting in enhanced anti-tumour effects. Doxorubicin (Dox), an immunogenic cell death (ICD) inducer, was combined with Bio-MnSe to form Bio-MnSe@Dox. This Bio-MnSe@Dox not only directly damaged tumour cells and induced tumour ICD but also promoted dendritic cell maturation, cytotoxic T lymphocyte infiltration, and NK cell recruitment, synergistically intensifying anti-tumour immune responses and suppressing tumour relapse and lung metastasis. Collectively, our findings propose an effective strategy for transforming 'cold' tumours to 'hot' ones, thereby advancing the development of anti-tumour immune drugs. STATEMENT OF SIGNIFICANCE: A biogenic MnSe (Bio-MnSe) nanocomposite was synthesized using Chlorella vulgaris as a bioreactor for enhanced immunotherapy of TNBC. Bio-MnSe demonstrated a stronger ability to activate the cGAS-STING signalling pathway and generate more ROS compared to pure Se nanoparticles and free Mn2+ ions. Apoptotic cells induced by Bio-MnSe released a significant amount of interferon, leading to the activation of T and natural killer (NK) cells, ultimately transforming immunologically 'cold' breast tumours to 'hot' tumours and enhancing the tumour's response to immune checkpoint inhibitors. The combination of Bio-MnSe with Dox or αPD-1 further enhanced the anti-tumour immune response, fostering dendritic cell maturation, infiltration of cytotoxic T lymphocytes, and recruitment of NK cells, thereby enhancing the anti-tumour immunotherapy of TNBC.
PubMed: 38936753
DOI: 10.1016/j.actbio.2024.06.025 -
Molecular Pharmaceutics Jun 2024Doxorubicin (DOX) is a common and highly effective chemotherapeutic. However, its use is limited by cardiotoxic effects and the lack of methods to detect these at early...
Doxorubicin (DOX) is a common and highly effective chemotherapeutic. However, its use is limited by cardiotoxic effects and the lack of methods to detect these at early time points. In the present study, we evaluated if [Cu]Cu-NODAGA-E[(cRGDyK)]2 positron emission tomography-computed tomography ([Cu]Cu-RGD PET/CT) could detect cardiotoxicity in a rat model of DOX-induced heart failure. Male Lewis rats were divided into two groups and treated with either a cumulative dose of 15 mg/kg of DOX or left untreated. Cardiac anatomy and function were assessed using magnetic resonance imaging at baseline and in week 8. [Cu]Cu-RGD PET/CT scans were performed in week 4. DOX treatment led to a decline in pump function as well as an increase in cardiac and thymic uptake of [Cu]Cu-RGD. In addition, DOX altered cardiac gene expression, led to infiltration of immune cells, reduced endothelial content, and increased interstitial fibrosis. Furthermore, concentrations of inflammatory plasma proteins were increased in the DOX group. In conclusion, DOX treatment resulted in the development of cardiotoxicity and heart failure, which could be detected using [Cu]Cu-RGD PET/CT at early time points. [Cu]Cu-RGD uptake in the myocardial septum and thymus predicted a low left ventricular ejection fraction in week 8.
PubMed: 38936409
DOI: 10.1021/acs.molpharmaceut.4c00272