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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 -
BioDrugs : Clinical Immunotherapeutics,... Jun 2024Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is one of the first line treatments for diffuse large B-cell lymphoma (DLBCL)....
BACKGROUND
Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is one of the first line treatments for diffuse large B-cell lymphoma (DLBCL). Rituximab comprises most of the treatment cost for this regimen; therefore, biosimilars, such as rituximab-abbs are crucial to provide affordable care. Although rituximab-abbs was studied primarily in follicular lymphoma, the Food and Drug Administration (FDA) approved this drug for all indications of the reference product on the basis of extrapolation. Effectiveness and safety data surrounding the use of rituximab-abbs in DLBCL is lacking.
OBJECTIVE
To evaluate the effectiveness and safety of rituximab-abbs and reference product rituximab as R-CHOP treatment for patients with DLBCL.
PATIENTS AND METHODS
This noninferiority (NI) study compared the 2-year overall survival (OS), overall response rate (ORR), and incidence of adverse events (AEs) between rituximab-abbs and its reference product (RP) in R-CHOP among adult patients with newly diagnosed DLBCL. The study inclusion period was from 1 January 2019 to 31 December 2020. Analyses were performed on the basis of a noninferiority lower limit of 10% for OS and ORR, and an upper limit of 10% for serious AEs.
RESULTS
There were 240 patients who received RP rituximab, while 295 patients received rituximab-abbs. The cohort had a mean age of 63.7±12.2 years and 43% were female. The 2-year OS was 81.0% and 79.6% (NI p < 0.01) while the ORR was 80.0% and 69.6% (NI p < 0.01), among the rituximab-abbs and rituximab groups, respectively. The incidence of infusion reaction AEs (NI p < 0.01) and noninfusion reaction AEs (NI p < 0.01) also met noninferiority.
CONCLUSIONS
We demonstrated that rituximab-abbs was noninferior to rituximab in both effectiveness and safety among patients receiving R-CHOP for DLBCL in this study. Long-term follow-up would be needed to confirm these results.
PubMed: 38935234
DOI: 10.1007/s40259-024-00666-1 -
Advanced Science (Weinheim,... Jun 2024Anthracyclines are chemotherapeutic drugs used to treat solid and hematologic malignancies. However, life-threatening cardiotoxicity, with cardiac dilation and heart...
Anthracyclines are chemotherapeutic drugs used to treat solid and hematologic malignancies. However, life-threatening cardiotoxicity, with cardiac dilation and heart failure, is a drawback. A combination of in vivo for single cell/nucleus RNA sequencing and in vitro approaches is used to elucidate the underlying mechanism. Genetic depletion and pharmacological blocking peptides on phosphatidylinositol binding clathrin assembly (PICALM) are used to evaluate the role of PICALM in doxorubicin-induced cardiotoxicity in vivo. Human heart tissue samples are used for verification. Patients with end-stage heart failure and chemotherapy-induced cardiotoxicity have thinner cell membranes compared to healthy controls do. Using the doxorubicin-induced cardiotoxicity mice model, it is possible to replicate the corresponding phenotype in patients. Cellular changes in doxorubicin-induced cardiotoxicity in mice, especially in cardiomyocytes, are identified using single cell/nucleus RNA sequencing. Picalm expression is upregulated only in cardiomyocytes with doxorubicin-induced cardiotoxicity. Amyloid β-peptide production is also increased after doxorubicin treatment, which leads to a greater increase in the membrane permeability of cardiomyocytes. Genetic depletion and pharmacological blocking peptides on Picalm reduce the generation of amyloid β-peptide. This alleviates the doxorubicin-induced cardiotoxicity in vitro and in vivo. In human heart tissue samples of patients with chemotherapy-induced cardiotoxicity, PICALM, and amyloid β-peptide are elevated as well.
PubMed: 38935046
DOI: 10.1002/advs.202401945 -
Combinatorial Chemistry & High... Jun 2024The purpose of this study was to analyze the relationship between serum indicators and high-throughput drug screening (HDS) results, aiming to achieve specific therapy...
AIM
The purpose of this study was to analyze the relationship between serum indicators and high-throughput drug screening (HDS) results, aiming to achieve specific therapy for hepatocellular carcinoma (HCC).
METHODS
This study recruited patients with HCC who underwent surgical resection at the Hepatobiliary Surgery Center of the First Affiliated Hospital of Chongqing Medical University from December 2019 to December 2021. HCC tissues were obtained from patients during surgery and subjected to in vitro cell culture, and then HDS testing was performed on the cultured tissue samples. We used Spearman's correlation analysis to examine the relationships between drug sensitivity results for anti-hepatocellular carcinoma drugs, other antitumor drugs, and serological indicators, the Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Systemic Immune Inflammatory Index (SII), Systemic Inflammatory Response Index (SIRI), Prognostic Nutritional Index (PNI), and Lymphocyte Monocyte Ratio (LMR). A significant correlation was considered when P<0.05 and |r|>0.40. Furthermore, linear regression analysis was conducted to elucidate the relationship between serological indicators and drug susceptibility, with significant results indicated by P<0.05 and R²≥0.50.
RESULTS
In this study, 82 patients with HCC who had undergone hepatectomy and completed in vitro cell culture and HDS testing were evaluated. Using Spearman's correlation with a significance threshold of P<0.05 and |r|>0.40, we identified significant associations between serological indicators and specific drug regimens: NLR correlated with 5-Fluorouracil, 5- Fluorouracil+Calcium folinate (FOLFOX4), and Capecitabine + Cisplatin (XP); PLR with FOLFOX4; SII with XP, FOLFOX4, Doxorubicin + Oxaliplatin (ADM+L-OHP); and SIRI with XP and FOLFOX4. No correlations were found between PNI or LMR and any drug inhibition rates. A comprehensive evaluation using linear regression analysis-which included variables such as sex, age, hepatitis B virus and liver cirrhosis status, size and number of lesions, alphafetoprotein, total bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, and prothrombin time, alongside NLR, PLR, SII, and SIRI was conducted in relation to drug regimens. This analysis revealed that NLR, SII, and SIRI are significant predictors of FOLFOX4 inhibition rate, while NLR predicts the inhibition rate of XP effectively. However, no significant links were established between molecular targeted drugs, other antitumor drugs, and serological indicators.
CONCLUSIONS
NLR, SII, and SIRI were correlated with FOLFOX4, and the higher the values of NLR, SII, and SIRI, the higher the in vitro inhibition of FOLFOX. Also, NLR was correlated with XP, and the higher the value of NLR, the higher the in vitro inhibition of XP.
PubMed: 38934277
DOI: 10.2174/0113862073305230240611091708 -
European Heart Journal. Case Reports Jun 2024Primary pericardial sarcomas are extremely rare malignancies. In this case of primary pericardial synovial sarcoma, we discuss the initial steps to work-up pericardial...
BACKGROUND
Primary pericardial sarcomas are extremely rare malignancies. In this case of primary pericardial synovial sarcoma, we discuss the initial steps to work-up pericardial effusions and review features that warrant more detailed investigation.
CASE SUMMARY
A 29-year-old male with no relevant past medical history presents with a few weeks of fatigue, dyspnoea, orthopnoea, leg swelling, and back pain. Transthoracic echocardiogram revealed pericardial effusion for which pericardiocentesis and drain placement were done. He was discharged with a diagnosis of post-viral pericarditis. He returned 5 months later with worsening symptoms. Advanced imaging with cardiac magnetic resonance imaging (CMR) showed heterogeneous pericardial mass later revealed to be a high-grade synovial sarcoma on biopsy. The patient was started on a doxorubicin-based chemotherapy regimen, but due to kidney dysfunction and multi-organ failure, he was transitioned to palliative care measures.
DISCUSSION
Transthoracic echocardiogram and computed tomography are often the initial tests of choice for pericardial effusions with pericardiocentesis recommended for effusions with tamponade physiology, for moderate-to-large effusions, or if there is concern for infection/neoplasm. Due to improved tissue characterization and spatial resolution, CMR and positron emission tomography should also be considered for atypical or recurrent pericardial effusions to assess for less common aetiologies such as malignancy.
PubMed: 38933365
DOI: 10.1093/ehjcr/ytae284 -
Pharmaceutics Jun 2024Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) are gaining traction in tumor theranostics for their effectiveness in encapsulating both imaging agents and...
Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) are gaining traction in tumor theranostics for their effectiveness in encapsulating both imaging agents and therapeutic drugs. While typically, similar hydrophilic molecules are encapsulated in either pure aqueous or organic environments, few studies have explored co-encapsulation of chemotherapeutic drugs and imaging agents with varying hydrophilicity and, consequently, constructed multifunctional ZIF-8 composite NPs for acid-responsive, near-infrared fluorescence imaging/chemotherapy combined tumor theranostics. Here, we present a one-pot method for the synthesis of uniform Cy5.5&DOX@ZIF-8 nanoparticles in mixed solvents, efficiently achieving simultaneous encapsulation of hydrophilic doxorubicin (DOX) and hydrophobic Cyanine-5.5 (Cy5.5). Surface decoration with dextran (Dex) enhanced colloidal stability and biocompatibility. The method significantly facilitated co-loading of Cy5.5 dyes and DOX drugs, endowing the composite NPs with notable fluorescent imaging capabilities and pH-responsive chemotherapy capacities. In vivo near-infrared fluorescence (NIRF) imaging in A549 tumor-bearing mice demonstrated significant accumulation of Cy5.5 at tumor sites due to enhanced permeability and retention (EPR) effects, with fluorescence intensities approximately 48-fold higher than free Cy5.5. Enhanced therapeutic efficiency was observed in composite NPs compared to free DOX, validating tumor-targeted capability. These findings suggest ZIF-8-based nanomedicines as promising platforms for multifunctional tumor theranostics.
PubMed: 38931943
DOI: 10.3390/pharmaceutics16060823 -
Pharmaceutics Jun 2024Microparticles are versatile carriers for controlled drug delivery in personalized, targeted therapy of various diseases, including cancer. The tumor microenvironment...
Microparticles are versatile carriers for controlled drug delivery in personalized, targeted therapy of various diseases, including cancer. The tumor microenvironment contains different infiltrating cells, including immune cells, which can affect the efficacy of antitumor drugs. Here, prototype microparticle-based systems for the delivery of the antitumor drug doxorubicin (DOX) were developed, and their cytotoxic effects on human epidermoid carcinoma cells and macrophages derived from human leukemia monocytic cells were compared in vitro. DOX-containing calcium carbonate microparticles with or without a protective polyelectrolyte shell and polyelectrolyte microcapsules of about 2.4-2.5 μm in size were obtained through coprecipitation and spontaneous loading. All the microstructures exhibited a prolonged release of DOX. An estimation of the cytotoxicity of the DOX-containing microstructures showed that the encapsulation of DOX decreased its toxicity to macrophages and delayed the cytotoxic effect against tumor cells. The DOX-containing calcium carbonate microparticles with a protective polyelectrolyte shell were more toxic to the cancer cells than DOX-containing polyelectrolyte microcapsules, whereas, for the macrophages, the microcapsules were most toxic. It is concluded that DOX-containing core/shell microparticles with an eight-layer polyelectrolyte shell are optimal drug microcarriers due to their low toxicity to immune cells, even upon prolonged incubation, and strong delayed cytotoxicity against tumor cells.
PubMed: 38931906
DOI: 10.3390/pharmaceutics16060785 -
Pharmaceutics May 2024Drug delivery selectivity is a challenge for cancer treatment. A hybrid pegylated pH-sensitive liposome-extracellular vesicle isolated from human breast cancer cell...
Drug delivery selectivity is a challenge for cancer treatment. A hybrid pegylated pH-sensitive liposome-extracellular vesicle isolated from human breast cancer cell MDA-MB-231 was developed to investigate its in vitro activity against breast cancer cells of different molecular profiles to overcome this inconvenience. The hybrid nanosystem was produced by film hydration, and doxorubicin (DOX) was encapsulated in this system using the ammonium sulfate gradient method. The characterization of this hybrid nanosystem revealed a mean diameter of 140.20 ± 2.70 nm, a polydispersity index of 0.102 ± 0.033, an encapsulation efficiency of doxorubicin of 88.9% ± 2.4, and a great storage stability for 90 days at 4 °C. The fusion of extracellular vesicles with liposomes was confirmed by nanoflow cytometry using PE-conjugated human anti-CD63. This hybrid nanosystem demonstrated cytotoxicity against human breast cancer cell lines with different molecular subtypes, enhanced anti-migration properties, and exhibited similar cellular uptake to the free DOX treatment. Preliminary acute toxicity assessments using Balb/C female mice indicated a median lethal dose of 15-17.5 mg/kg, with no evidence of splenic, liver, heart, bone marrow, and renal damage at a dose of 15 mg/kg. These findings suggest the hybrid formulation as a versatile nanocarrier for the treatment of various breast cancer subtypes.
PubMed: 38931861
DOI: 10.3390/pharmaceutics16060739