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Journal of Nanobiotechnology Aug 2023Inhibition of tumor growth and normalization of immune responses in the tumor microenvironment (TME) are critical issues for improving cancer therapy. However, in the...
Inhibition of tumor growth and normalization of immune responses in the tumor microenvironment (TME) are critical issues for improving cancer therapy. However, in the treatment of glioma, effective nanomedicine has limited access to the brain because of the blood-brain barrier (BBB). Previously, we demonstrated nano-sized ginseng-derived exosome-like nanoparticles (GENs) consisting of phospholipids including various bioactive components, and evaluated anti-tumor immune responses in T cells and Tregs to inhibit tumor progression. It was found that the enhanced targeting ability of GENs to the BBB and glioma induced a significant therapeutic effect and exhibited strong efficacy in recruiting M1 macrophage expression in the TME. GENs were demonstrated to be successful candidates in glioma therapeutics both in vitro and in vivo, suggesting excellent potential for inhibiting glioma progression and regulating tumor-associated macrophages (TAMs).
Topics: Humans; Blood-Brain Barrier; Tumor Microenvironment; Exosomes; Panax; Glioma; Nanoparticles; Cell Line, Tumor
PubMed: 37542285
DOI: 10.1186/s12951-023-02006-x -
Journal of Pharmaceutical Analysis Jul 2023Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural...
Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.
PubMed: 37577382
DOI: 10.1016/j.jpha.2023.04.013 -
Phytomedicine : International Journal... Jan 2024Pancreatic cancer is an extremely malignant digestive tumor, however, owing to its high drug resistance of pancreatic cancer, the search for more effective...
BACKGROUND
Pancreatic cancer is an extremely malignant digestive tumor, however, owing to its high drug resistance of pancreatic cancer, the search for more effective anti-pancreatic cancer drugs is urgently needed. Lycorine, an alkaloid of natural plant origin, exerts antitumor effects on a variety of tumors.
PURPOSE
This study aimed to investigate the therapeutic effect of lycorine on pancreatic cancer and elucidate its potential molecular mechanism.
METHODS
Two pancreatic cancer cell lines, PANC-1 and BxPC-3, were used to investigate the therapeutic effects of lycorine on pancreatic cancer in vitro using the CCK8 assay, colony formation assay, 5-Ethynyl-2'- deoxyuridine (EdU) incorporation assay, flow cytometry, and western blotting. Transcriptome sequencing and gene set enrichment analysis (GSEA) were used to analyze the differentially expressed genes and pathways after lycorine treatment. Molecular docking, quantitative real-time PCR (qRT-PCR), oil red O staining, small interfering RNA (siRNA) transfection, and other experiments were performed to further validate the differentially expressed genes and pathways. In vivo experiments were conducted to investigate lycorine's inhibitory effects and toxicity on pancreatic cancer using a tumor-bearing mouse model.
RESULTS
Lycorine inhibited the proliferation of pancreatic cancer cells, caused G2/M phase cycle arrest and induced apoptosis. Transcriptome sequencing and GSEA showed that lycorine inhibition of pancreatic cancer was associated with fatty acid metabolism, and aldehyde dehydrogenase 3A1 (ALDH3A1) was a significantly enriched target in the fatty acid metabolism process. ALDH3A1 expression was significantly upregulated in pancreatic cancer and was closely associated with prognosis. Molecular docking showed that lycorine binds strongly to ALDH3A1. Further studies revealed that lycorine inhibited the fatty acid oxidation (FAO) process in pancreatic cancer cells and induced cell growth inhibition and apoptosis through ALDH3A1. Lycorine also showed significant suppressive effects in tumor-bearing mice. Importantly, it did not result in significant toxicity to liver and kidney of mice, demonstrating its therapeutic potential as a safe antitumor agent.
CONCLUSION
Lycorine inhibited pancreatic cancer cell proliferation, blocked the cell cycle, and induced apoptosis by targeting ALDH3A1. FAO inhibition was identified for the first time as a possible mechanism for the anticancer effects of lycorine. These findings enrich the theory of targeted therapy for pancreatic cancer, expand our understanding of the pharmacological targets of lycorine, and provide a reference for exploring its natural components.
Topics: Animals; Mice; Molecular Docking Simulation; Cell Line, Tumor; Transcriptome; Cell Proliferation; Antineoplastic Agents; Pancreatic Neoplasms; Apoptosis; RNA, Small Interfering; Fatty Acids
PubMed: 37839227
DOI: 10.1016/j.phymed.2023.155128 -
Vaccines Jul 2023Plant virus nanoparticles (PVNPs) have garnered considerable interest as a promising nanotechnology approach to combat cancer. Owing to their biocompatibility,... (Review)
Review
Plant virus nanoparticles (PVNPs) have garnered considerable interest as a promising nanotechnology approach to combat cancer. Owing to their biocompatibility, stability, and adjustable surface functionality, PVNPs hold tremendous potential for both therapeutic and imaging applications. The versatility of PVNPs is evident from their ability to be tailored to transport a range of therapeutic agents, including chemotherapy drugs, siRNA, and immunomodulators, thereby facilitating targeted delivery to the tumor microenvironment (TME). Furthermore, PVNPs may be customized with targeting ligands to selectively bind to cancer cell receptors, reducing off-target effects. Additionally, PVNPs possess immunogenic properties and can be engineered to exhibit tumor-associated antigens, thereby stimulating anti-tumor immune responses. In conclusion, the potential of PVNPs as a versatile platform for fighting cancer is immense, and further research is required to fully explore their potential and translate them into clinical applications.
PubMed: 37631846
DOI: 10.3390/vaccines11081278 -
Journal of Ethnopharmacology Nov 2023Traditional Chinese medicine has accumulated valuable experience in the treatment of inflammatory diseases caused by Ferroptosis. Jing Jie and Fang Feng are two warm...
ETHNOPHARMACOLOGICAL RELEVANCE
Traditional Chinese medicine has accumulated valuable experience in the treatment of inflammatory diseases caused by Ferroptosis. Jing Jie and Fang Feng are two warm acrid exterior-resolving medicinal herbs that play an important role in the prevention and treatment of inflammatory diseases. The pairing of the two forms a drug pair (Jing-Fang) that shows significant advantages in fighting oxidative stress and inflammation. Whereas, the underlying mechanism needs to be further improved.
AIM OF THE STUDY
In this study, the anti-inflammatory effect of Jing-Fang n-butanol extract (JFNE) and its isolate C (JFNE-C) on LPS-induced RAW264.7 cells and the regulation effect on ferroptosis were investigated, and also the mechanism of STAT3/p53/SLC7A11 signal pathway-related to ferroptosis.
MATERIALS AND METHODS
Jing-Fang n-butanol extract (JFNE) and its active isolate (JFNE-C) were extracted and isolated. LPS-induced inflammation model in RAW264.7 cells was established to assess the anti-inflammatory effect and ferroptosis mechanism of JFNE and JFNE-C. The levels of interleukin 6 (IL-6), interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were measured. The activity levels of antioxidant substances such as glutathione (GSH), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were measured. Flow cytometry, immunofluorescence and transmission electron microscopy were used to assess ROS level, ferrous iron content and mitochondrial morphological changes. Through administration of Ferrostatin-1 (Fer-1), an ferroptosis inhibitor, to verify the role of JFNE and JFNE-C in regulating ferroptosis in resistance to the inflammatory response. Western blotting was used to determine whether the JFNE and JFNE-C exerted effectiveness by modulating the STAT3/p53/SLC7A11 signaling pathway. In addition, the important role of STAT3/p53/SLC7A11 signaling pathway in drug regulation of ferroptosis and inflammatory response was further validated by administration of S3I-201 (STAT3 inhibitor). Finally, high performance liquid chromatography-mass spectrometry (HPLC-MS) was used to determine the major active components of JFNE and JFNE-C.
RESULTS
The results showed that treated with JFNE-C significantly reduced the contents of interleukin 6 (IL-6), interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in the supernatant of LPS-induced RAW264.7 cells. The pretreatment with JFNE and JFNE-C significantly decreased intracellular oxidative stress levels, including reductions of ROS and MDA levels, and increases of GSH-Px, SOD and GSH levels. In addition, JFNE and JFNE-C obviously reduced intracellular ferrous iron level, and JFNE-C was effective in alleviating mitochondrial damage which includes mitochondrial shrinkage, increase of mitochondrial membrane density and reduction and absence of cristae. Further results indicated that JFNE-C showed a reduction of p53 and p-p53 protein levels in LPS-induced RAW264.7 cells, while significantly increasing the protein expression levels of STAT3, p-STAT3, SLC7A11 and GPX4. Besides, JFNE-C contains key active substances such as 5-O-Methylvisammioside, Hesperidin and Luteolin. Remarkably, this is different from JFNE, which is rich in nutrients such as sucrose, choline and various amino acids.
CONCLUSION
These results suggest that JFNE and JFNE-C may exert anti-inflammatory effect through activating the STAT3/p53/SLC7A11 signaling pathway to inhibit ferroptosis.
Topics: Humans; 1-Butanol; Interleukin-6; Tumor Necrosis Factor-alpha; Interleukin-1beta; Lipopolysaccharides; Butanols; Ferroptosis; Reactive Oxygen Species; Tumor Suppressor Protein p53; Signal Transduction; Inflammation; Macrophages; Plant Extracts; Anti-Inflammatory Agents; Superoxide Dismutase
PubMed: 37315642
DOI: 10.1016/j.jep.2023.116689 -
Biomedicines Aug 2023Ovarian cancer is the leading cause of gynecological death worldwide, and its poor prognosis and high mortality seriously affect the life of ovarian cancer patients.... (Review)
Review
Ovarian cancer is the leading cause of gynecological death worldwide, and its poor prognosis and high mortality seriously affect the life of ovarian cancer patients. Runt-related transcription factor 1 (RUNX1) has been widely studied in hematological diseases and plays an important role in the occurrence and development of hematological diseases. In recent years, studies have reported the roles of RUNX1 in solid tumors, including the significantly increased expression of RUNX1 in ovarian cancer. In ovarian cancer, the dysregulation of the RUNX1 signaling pathway has been implicated in tumor progression, metastasis, and response to therapy. At the same time, the decreased expression of RUNX1 in ovarian cancer can significantly improve the sensitivity of clinical chemotherapy and provide theoretical support for the subsequent diagnosis and treatment target of ovarian cancer, providing prognosis and treatment options to patients with ovarian cancer. However, the role of RUNX1 in ovarian cancer remains unclear. Therefore, this article reviews the relationship between RUNX1 and the occurrence and development of ovarian cancer, as well as the closely regulated signaling pathways, to provide some inspiration and theoretical support for future research on RUNX1 in ovarian cancer and other diseases.
PubMed: 37760803
DOI: 10.3390/biomedicines11092357 -
Drug Delivery Dec 2023Brain tumor accounts for about 1.6% of incidence and 2.5% of mortality of all tumors, and the median survival for brain tumor patients is only about 20 months. The... (Review)
Review
Brain tumor accounts for about 1.6% of incidence and 2.5% of mortality of all tumors, and the median survival for brain tumor patients is only about 20 months. The treatment for brain tumor still faces many challenges, such as the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), the overexpressed efflux pumps, the infiltration, invasion, high heterogeneity of tumor cells, drug resistance and immune escape caused by tumor microenvironment (TME) and cancer stem cells (CSC). This review attempts to clarify the challenges for multi-functional nano drug delivery systems (NDDS) to cross the BBB and target the cancer cells or organelles, and also provides a brief description of the different types of targeted multi-functional NDDS that have shown potential for success in delivering drugs to the brain. Further, this review also summarizes the research progress of multi-functional NDDS in the combination therapy of brain tumors from the following sections, the combination of chemotherapy drugs, chemotherapy-chemodynamic combination therapy, chemotherapy-immunization combination therapy, and chemotherapy-gene combination therapy. We also provide an insight into the recent advances in designing multi-functional NDDS for combination therapy.
Topics: Humans; Antineoplastic Agents; Drug Delivery Systems; Brain Neoplasms; Brain; Blood-Brain Barrier; Tumor Microenvironment
PubMed: 36597214
DOI: 10.1080/10717544.2022.2154409 -
Immunopharmacology and Immunotoxicology Dec 2023Rapidly growing evidence suggests that immune cells play a key role in determining tumor progression. Tumor cells are surrounded by a microenvironment composed of... (Review)
Review
OBJECTIVES
Rapidly growing evidence suggests that immune cells play a key role in determining tumor progression. Tumor cells are surrounded by a microenvironment composed of different cell populations including immune cells. The cross talk between tumor cells and the neighboring microenvironment is an important factor to take into account while designing tumor therapies. Despite significant advances in immunotherapy strategies, a relatively small proportion of patients have successfully responded to them. Therefore, the search for safe and efficient drugs, which could be used alongside conventional therapies to boost the immune system against tumors, is an ongoing need. In the present work, the modulatory effects of melatonin on different components of tumor immune microenvironment are reviewed.
METHODS
A thorough literature review was performed in PubMed, Scopus, and Web of Science databases. All published papers in English on tumor immune microenvironment and the relevant modulatory effects of melatonin were scrutinized.
RESULTS
Melatonin modulates macrophage polarization and prevents M2 induction. Moreover, it prevents the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) and prevents cancer cell stemness. In addition, it can affect the payload composition of tumor-derived exosomes (TEXs) and their secretion levels to favor a more effective anti-tumor immune response. Melatonin is a safe molecule that affects almost all components of the tumor immune microenvironment and prevents them from being negatively affected by the tumor.
CONCLUSION
Based on the effects of melatonin on normal cells, tumor cells and microenvironment components, it could be an efficient compound to be used in combination with conventional immune-targeted therapies to increase their efficacy.
Topics: Humans; Melatonin; Neoplasms; Fibroblasts; Cancer-Associated Fibroblasts; Immunotherapy; Tumor Microenvironment
PubMed: 37489565
DOI: 10.1080/08923973.2023.2239489 -
Cell Reports. Medicine Feb 2024Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade has become a mainstay of cancer immunotherapy. Targeting the PD-1/PD-L1 axis with small...
Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade has become a mainstay of cancer immunotherapy. Targeting the PD-1/PD-L1 axis with small molecules is an attractive approach to enhance antitumor immunity. Here, we identified a natural marine product, benzosceptrin C (BC), that enhances the cytotoxicity of T cells to cancer cells by reducing the abundance of PD-L1. Furthermore, BC exerts its antitumor effect in mice bearing MC38 tumors by activating tumor-infiltrating T cell immunity. Mechanistic studies suggest that BC can prevent palmitoylation of PD-L1 by inhibiting DHHC3 enzymatic activity. Subsequently, PD-L1 is transferred from the membrane to the cytoplasm and cannot return to the membrane via recycling endosomes, triggering lysosome-mediated degradation of PD-L1. Moreover, the combination of BC and anti-CTLA4 effectively enhances antitumor T cell immunity. Our findings reveal a previously unrecognized antitumor mechanism of BC and represent an alternative immune checkpoint blockade (ICB) therapeutic strategy to enhance the efficacy of cancer immunotherapy.
Topics: Animals; Mice; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Neoplasms; Lysosomes; Imidazoles; Pyrroles
PubMed: 38237597
DOI: 10.1016/j.xcrm.2023.101357 -
Proceedings of the National Academy of... Oct 2023Metastatic cancer accounts for 90% of all cancer-related deaths and continues to be one of the toughest challenges in cancer treatment. A growing body of data indicates...
Metastatic cancer accounts for 90% of all cancer-related deaths and continues to be one of the toughest challenges in cancer treatment. A growing body of data indicates that S100A9, a major regulator of inflammation, plays a central role in cancer progression and metastasis, particularly in the lungs, where S100A9 forms a premetastatic niche. Thus, we developed a vaccine against S100A9 derived from plant viruses and virus-like particles. Using multiple tumor mouse models, we demonstrate the effectiveness of the S100A9 vaccine candidates in preventing tumor seeding within the lungs and outgrowth of metastatic disease. The elicited antibodies showed high specificity toward S100A9 without cross-reactivity toward S100A8, another member of the S100A family. When tested in metastatic mouse models of breast cancer and melanoma, the vaccines significantly reduced lung tumor nodules after intravenous challenge or postsurgical removal of the primary tumor. Mechanistically, the vaccines reduce the levels of S100A9 within the lungs and sera, thereby increasing the expression of immunostimulatory cytokines with antitumor function [(interleukin) IL-12 and interferonγ] while reducing levels of immunosuppressive cytokines (IL-10 and transforming growth factorβ). This also correlated with decreased myeloid-derived suppressor cell populations within the lungs. This work has wide-ranging impact, as S100A9 is overexpressed in multiple cancers and linked with poor prognosis in cancer patients. The data presented lay the foundation for the development of therapies and vaccines targeting S100A9 to prevent metastasis.
Topics: Humans; Mice; Animals; Viral Vaccines; Calgranulin B; Lung Neoplasms; Calgranulin A; Lung; Cytokines
PubMed: 37844250
DOI: 10.1073/pnas.2221859120