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1.
Phytother Res ; 37(10): 4655-4673, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37525965

ABSTRACT

The worldwide overall 5-year survival rate of esophageal squamous cell carcinoma (ESCC) patients is less than 20%, and novel therapeutic strategies for these patients are urgently needed. Harmine is a natural ß-carboline alkaloid, which received great interest in cancer research because of its biological and anti-tumor activities. The aim of this study is to examine the effects of harmine on ESCC and its mechanism. We investigated the effects of harmine on proliferation, cell cycle, apoptosis, and tumor growth in vivo. RNA sequencing (RNA-seq), real-time PCR, and western blotting were used to detect the mechanism. Harmine inhibited ESCC cell growth in vitro and tumor growth in vivo. Differentially expressed genes in harmine-treated ESCC cells were mainly involved in protein processing in the endoplasmic reticulum (ER). Real-time PCR and western blotting confirmed harmine-induced cellular ER stress. CRISPR-Cas9 knockout of C/EBP homologous protein (CHOP) abolished harmine-induced expression of death receptor 5 and apoptosis. Harmine also induced the expression of CHOP-mediated sestrin-2, which in turn contributes to autophagosome formation via suppressing the AMP-activated protein kinase-protein kinase B-mammalian target of rapamycin signaling pathway. In conclusion, our results demonstrate that harmine inhibits the growth of ESCC through its regulation of ER stress, suggesting that it is a promising candidate for ESCC treatment.

2.
Int J Mol Sci ; 23(21)2022 Oct 31.
Article in English | MEDLINE | ID: mdl-36362052

ABSTRACT

Neutrophils play a pivotal role in innate immunity by releasing neutrophils extracellular traps (NETs). Excessive NETs are detrimental to the local tissue and further exacerbate inflammation. Protein arginine deiminases (PAD) mediate histone citrullination and NET formation that, in turn, exacerbate endotoxin shock damages. In this study, we further investigated the molecular mechanism underlying PAD and NETs in endotoxic stress in mice. The control group mice were injected with solvent, the LPS endotoxic shock group mice were intraperitoneally injected with LPS at 35 mg/kg only, while the LPS and PAD inhibitor YW3-56 treatment group mice were injected with YW3-56 at 10 mg/kg prior to the LPS injection. YW3-56 significantly prolonged the survival time of the LPS-treated mice. NETs, cfDNA, and inflammatory factors were detected by ELISA in serum, paitoneal cavity, and lung at 24 h after LPS administration. Lung injuries were detected by immunostaining, and lung tissue transcriptomes were analyzed by RNA-seq at 24 h after LPS administration. We found that YW3-56 altered neutrophil tissue homeostasis, inhibited NET formation, and significantly decreased cytokines (IL-6, TNFα and IL-1ß) levels, cytokines gene expression, and lung tissue injury. In summary, NET formation inhibition offers a new avenue to manage inflammatory damages under endotoxic stress.


Subject(s)
Extracellular Traps , Inflammation , Shock, Septic , Animals , Mice , Cytokines/metabolism , Extracellular Traps/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/toxicity , Lipopolysaccharides/metabolism , Neutrophils/metabolism , Protein-Arginine Deiminases/antagonists & inhibitors , Protein-Arginine Deiminases/metabolism , Shock, Septic/chemically induced , Shock, Septic/drug therapy , Shock, Septic/metabolism
3.
Front Immunol ; 13: 960094, 2022.
Article in English | MEDLINE | ID: mdl-36389744

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed serious threats to global health and economy and calls for the development of safe treatments and effective vaccines. The receptor-binding domain in the spike protein (SRBD) of SARS-CoV-2 is responsible for its binding to angiotensin-converting enzyme 2 (ACE2) receptor. It contains multiple dominant neutralizing epitopes and serves as an important antigen for the development of COVID-19 vaccines. Here, we showed that dimeric SRBD-Fc and tetrameric 2xSRBD-Fc fusion proteins bind ACE2 with different affinity and block SARS-CoV-2 pseudoviral infection. Immunization of mice with SRBD-Fc fusion proteins elicited high titer of RBD-specific antibodies with robust neutralizing activity against pseudoviral infections. As such, our study indicates that the polymeric SRBD-Fc fusion protein can serve as a treatment agent as well as a vaccine for fighting COVID-19.


Subject(s)
Antibodies, Neutralizing , COVID-19 , Humans , Mice , Animals , Angiotensin-Converting Enzyme 2 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Viral Envelope Proteins , COVID-19 Vaccines , Membrane Glycoproteins/metabolism
4.
Int J Mol Sci ; 22(20)2021 Oct 12.
Article in English | MEDLINE | ID: mdl-34681647

ABSTRACT

Increasing the level of reactive oxygen species (ROS) in cancer cells has been suggested as a viable approach to cancer therapy. Our previous study has demonstrated that mitochondria-targeted flavone-naphthalimide-polyamine conjugate 6c elevates the level of ROS in cancer cells. However, the detailed role of ROS in 6c-treated cancer cells is not clearly stated. The biological effects and in-depth mechanisms of 6c in cancer cells need to be further investigated. In this study, we confirmed that mitochondria are the main source of 6c-induced ROS, as demonstrated by an increase in 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSox fluorescence. Compound 6c-induced mitochondrial ROS caused mitochondrial dysfunction and lysosomal destabilization confirmed by absolute quantitation (iTRAQ)-based comparative proteomics. Compound 6c-induced metabolic pathway dysfunction and lysosomal destabilization was attenuated by N-acetyl-L-cysteine (NAC). iTRAQ-based comparative proteomics showed that ROS regulated the expression of 6c-mediated proteins, and treatment with 6c promoted the formation of autophagosomes depending on ROS. Compound 6c-induced DNA damage was characterized by comet assay, p53 phosphorylation, and γH2A.X, which was diminished by pretreatment with NAC. Compound 6c-induced cell death was partially reversed by 3-methyladenine (3-MA), bafilomycin (BAF) A1, and NAC, respectively. Taken together, the data obtained in our study highlighted the involvement of mitochondrial ROS in 6c-induced autophagic cell death, mitochondrial and lysosomal dysfunction, and DNA damage.


Subject(s)
Autophagic Cell Death/drug effects , DNA Damage/drug effects , Lysosomes/metabolism , Mitochondria/metabolism , Naphthalimides/pharmacology , Reactive Oxygen Species/metabolism , Acetylcysteine/pharmacology , Adenine/analogs & derivatives , Adenine/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Autophagosomes/metabolism , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Hep G2 Cells , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Microtubule-Associated Proteins/metabolism , Naphthalimides/chemistry , Proteome/analysis , Proteomics/methods , Sequestosome-1 Protein/metabolism
5.
Cancer Lett ; 519: 30-45, 2021 10 28.
Article in English | MEDLINE | ID: mdl-34166768

ABSTRACT

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Oxidative phosphorylation (OXPHOS) has attracted a considerable attention in CRC. It is of great interest to explore novel therapies that inhibit OXPHOS for CRC treatment. Compound 6c is a novel naphthalimide derivative. However, the effects of 6c on CRC and the underlying mechanism are unclear. In this study, 6c suppressed CRC tumor growth and metastasis. RNA-seq data showed that 6c triggered the inhibition of OXPHOS and tricarboxylic acid cycle. 6c specifically inhibited mitochondrial complex III activity and the expression of isocitrate dehydrogenase 2 (IDH2), resulting in oxidative stress. Antioxidants reversed 6c-induced cell death, senescence, and autophagosomes formation. 6c inhibited autophagy flux; however, pretreatment with autophagy inhibitors resulted in the reduction of 6c-induced cytoplasmic vacuolization and proliferation inhibition. Moreover, combinatory treatment of 6c and mitoxantrone (MIT) showed stronger inhibitory effects on CRC compared with the single agent. Downregulation of IDH2 induced reactive oxygen species production, leading to MIT accumulation and autophagic cell death after co-treatment with 6c and MIT. In summary, our findings indicated 6c as a promising candidate for CRC treatment.


Subject(s)
Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Isocitrate Dehydrogenase/metabolism , Mitoxantrone/pharmacology , Naphthalimides/pharmacology , Oxidative Phosphorylation/drug effects , Animals , Antioxidants/metabolism , Autophagy/drug effects , Cell Death/drug effects , Cell Line, Tumor , Citric Acid Cycle/drug effects , Down-Regulation/drug effects , HCT116 Cells , HT29 Cells , Humans , Mice , Mice, Inbred BALB C , Mitochondria/drug effects , Mitochondria/metabolism , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism
6.
Phytomedicine ; 85: 153530, 2021 May.
Article in English | MEDLINE | ID: mdl-33761445

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Metastasis is the major cause of death in patients with CRC. Lycorine, the phenanthridine alkaloid most commonly found in spp of the Amaryllidaceae family, has shown promising anticancer activities with minor side effects. However, the effects and the detailed mechanism of lycorine against metastasis of CRC remains unclear. STUDY DESIGN/METHODS: The purpose of this study was to investigate the effects of lycorine on CRC and characterize the molecular mechanisms observed in lycorine-treated CRC cells using RNA-sequencing. MTT assay, colony formation assay, acridine orange/ethidium bromide (AO/EB) staining and Annexin V-FITC/Propidium iodide (PI) staining were conducted to examine the effects of lycorine on cell proliferation and apoptosis in CRC cells. RNA sequencing, real-time PCR assays and western blot were performed. Migration and invasion abilities of lycorine-treated CRC cells were investigated by wound healing and transwell invasion assays. The mouse CRC lung metastasis model was established and was used to detect the effect of lycorine on CRC in vivo. RESULTS: Our results demonstrated that lycorine inhibited the proliferation and colony formation of CRC cells in a concentration-dependent manner. AO/EB staining and Annexin V-FITC/PI staining showed that lycorine induced apoptosis in a concentration-dependent manner. Lycorine also reduced lung metastasis of CRC in vivo. Moreover, transcriptomic analysis suggested that lycorine regulated the expression of 3556 genes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was implicated according to the differentially expressed genes (DEGs), and multiple pathways including those of mitogen-activated protein kinase (MAPK), relaxin, Ras, phosphatidylinositol 3­kinase (PI3K)-protein kinase B (Akt) and Wnt/ß-catenin were selected by functional enrichment analyses. Furthermore, based on transcriptomic analysis, we found that the tumor necrosis factor (TNF) pathway and endoplasmic reticulum stress were responsible for lycorine-induced apoptosis. CONCLUSIONS: These results obtained in this study demonstrated that lycorine has the potential to suppress CRC in vitro and in vivo through the lycorine-regulated multiple signaling pathways.


Subject(s)
Amaryllidaceae Alkaloids/pharmacology , Colorectal Neoplasms/drug therapy , Phenanthridines/pharmacology , RNA-Seq , Signal Transduction/drug effects , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/pathology , Endoplasmic Reticulum Stress/drug effects , Humans , Male , Mice , Mice, Inbred BALB C , Neoplasm Metastasis , Phosphatidylinositol 3-Kinases/metabolism
7.
Cancers (Basel) ; 12(3)2020 Feb 25.
Article in English | MEDLINE | ID: mdl-32106543

ABSTRACT

Colorectal cancer (CRC) is one of the most prevalent cancers due to its frequency and high rate of mortality. Polyamine-vectorized anticancer drugs possess multiple biological properties. Of these drugs, 9F has been shown to inhibit tumor growth and the metastasis of hepatocellular carcinoma. This current study aims to investigate the effects of 9F on CRC and determine its molecular mechanisms of action. Our findings demonstrate that 9F inhibits CRC cell growth by inducing apoptosis and cell cycle arrest, and suppresses migration, invasion and angiogenesis in vitro, resulting in the inhibition of tumor growth and metastasis in vivo. Based on RNA-seq data, further bioinformatic analyses suggest that 9F exerts its anticancer activities through p53 signaling, which is responsible for the altered expression of key regulators of the cell cycle, apoptosis, the epithelial-to-mesenchymal transition (EMT), and angiogenesis. In addition, 9F is more effective than amonafide against CRC. These results show that 9F can be considered as a potential strategy for CRC treatment.

8.
Medchemcomm ; 9(8): 1377-1385, 2018 Aug 01.
Article in English | MEDLINE | ID: mdl-30151093

ABSTRACT

Naphthalenetetracarboxylic diimide (NDI) is widely used as a photoelectric material in the field of medicine. A series of asymmetric naphthalene diimide derivatives were synthesized and evaluated for their anticancer properties by various experimental assays. As the representative compound, 3c exerted significantly greater inhibitory effects on hepatoma cells SMMC-7721 and Hep G2 with an IC50 value of 1.48 ± 0.43 µM and 1.70 ± 0.53 µM, respectively, than normal hepatocytes QSG-7701 with an IC50 value of 7.11 ± 0.08 µM. Treatment with compound 3c (3 µM) for 48 h resulted in apoptosis of SMMC-7721 cells and Hep G2 cells with 52.1% and 67.8% apoptotic cells, respectively. Compound 3c induced autophagy and suppressed the migration of hepatoma cells in a concentration-dependent manner, resulting from the generation of reactive oxygen species (ROS). Based on its biological ability, compound 3c was considered as a potent anticancer agent.

9.
J Med Chem ; 61(15): 6814-6829, 2018 Aug 09.
Article in English | MEDLINE | ID: mdl-29990424

ABSTRACT

Polyamine derivatives have a promising prospect in dealing with disseminated tumor cells, a major obstacle in cancer therapy. To develop a bifunctional polyamine derivative that can serve as a fluorescent probe and an antimetastatic agent, three kinds of polyamine conjugates with benzo[ cd]indol-2(1 H)-one as a scaffold were designed and synthesized. Compound 5e was selected as a lead by in vitro screening. Two animal models demonstrated that 5e inhibited pulmonary metastasis and tumor growth. As a fluorescent probe, 5e might partially enter cells via a polyamine transporter and subsequently localize in the lysosome. Mechanistic investigations demonstrated the interdependence of 5e-triggered apoptosis and autophagy. Compound 5e modulated the expression of LC3-II, p62, cathepsins, and the expression of capases 3, caspase 8, Bcl-2, and p53. The SSAT-mediated Akt/ß-catenin pathways were also inhibited by 5e. The dual features of 5e make it a worthwhile lead compound for further structural optimization.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Indoles/chemistry , Lysosomes/drug effects , Lysosomes/metabolism , Polyamines/chemistry , Polyamines/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Neoplasm Metastasis
10.
Eur J Med Chem ; 143: 1732-1743, 2018 Jan 01.
Article in English | MEDLINE | ID: mdl-29133040

ABSTRACT

A new class of polyamine analogues modified by alkylation at the terminal of the polyamine chain has been synthesized and their structures were determined by 1H NMR, 13C NMR, ESI-MS and elemental analysis. As the representative compound, 3f displayed a broad spectrum of anti-cancer effects by MTT assays. Tumor xenograft model and pulmonary metastasis model showed that compound 3f significantly suppressed tumor growth and metastasis in vivo, which was more stronger than the reference drug amonafide. Molecular mechanisms indicated that compound 3f exhibited antiproliferative activities and induced the generation of reactive oxygen species (ROS), which resulted in the occurrence of autophagy. The downregulated expression of MMP-9 and ß-catenin by compound 3f accounted for the inhibition of migration. Taken altogether, the in vitro and in vivo biological evaluations corroborated compound 3f to be an effective anticancer agent.


Subject(s)
Antineoplastic Agents/pharmacology , Polyamines/pharmacology , Alkylation , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Polyamines/chemical synthesis , Polyamines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
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