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Cell viability of GC cells after PMI treatment was determined using an MTT assay. (A) Chemical structure of PMI. (B) Human GC cells were treated with various concentrations of PMI, and cell viability was evaluated using the MTT assay. A concentration of 50 µM of PMI was used as the optimal concentration based on viability results for a non-toxic dose. GC, gastric cancer; PMI, peiminine.
Source publication
Gastric cancer (GC) is one of the most common malignancies of the digestive tract. Adriamycin (ADR) has been widely utilized in various chemotherapy regimens for treating GC, yet its long-term application may increase drug resistance resulting in treatment failure. Increasing evidence shows that bioactive natural products can be used as chemotherap...
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Context 1
... (PMI) (Fig. 1A), is a biologically active component extracted from Fritillaria walujewii Regel of the Liliaceae family known as Xinjiang-Bei-Mu. Along with other alkaloids extracted from Fritillaria, PMI was reported to show biological effects as an antitussive and a relaxant of bronchial smooth muscle (12,13). In addition, PMI was found to suppress ...
Context 2
... of PMI on the cell viability of the GC cell lines. To determine the cell cytotoxicity of PMI, we determined the cell viability using MTT assay, in which GC cell lines were treated with PMI at concentrations of 12.5, 25, 50, 100, 200 and 400 µM, respectively. Compared to the vehicle (DMSO), a high dose of PMI partly inhibited cell growth (Fig. 1B). A concentration of 50.0 µM of PMI was used as the optimal concentration based on viability results for a non-toxic ...
Citations
... Imperialine is a promising novel anticancer compound against NSCLC in vitro and in vivo (Lin et al., 2020). As reported in previous studies, the natural product peiminine represses various types of cancers including colorectal, lung and gastric cancer (Tang et al., 2018;Zheng et al., 2016Zheng et al., , 2017. Peiminine has been previously demonstrated to reduce the viability of HepG2 cells in a time-and dose-dependent manner and had an IC 50 of 4.58 lg/mL at 24 h. ...
Fritillaria cirrhosa D. Don is a well-known medicinal plant of Kashmir Himalaya. Traditionally, it has been used to treat several diseases, including cancer. However, the molecular mechanism behind anticancer activity remains unclear. Therefore, in the present study, we have performed high performance- liquid chromatography-mass spectrometry (HR-LC/MS), network pharmacology, molecular docking and molecular dynamic (MD) simulation methods were used to explore the underlying molecular mechanism of F. cirrhosa for the treatment of breast cancer (BC). The targets of F. cirrhosa for treating BC were predicted using databases like SwissTargetPrediction, Gene Cards and OMIM. Protein–protein interaction analysis and network construction were performed using the Search Tool for the Retrieval of Interacting Genes/Proteins programme, and analysis of Gene Ontology term enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment was done using the Cytoscape programme. In addition, molecular docking was used to investigate intermolecular interactions between the compounds and the proteins using the Autodock tool. MD simulations studies were also used to explore the stability of the representative AKT1 gene peiminine and Imperialine-3-b-glucoside. In addition, experimental treatment of F. cirrhosa was also verified. HR-LC/MS detected the presence of several secondary metabolites. Afterward, molecular docking was used to verify the effective activity of the active ingredients against the prospective targets. Additionally, Peiminine and Imperialine-3-b-glucoside showed the highest binding energy score against AKT-1 (–12.99kcal/mol and −12.08kcal/mol). AKT1 with Peiminine and Imperialine-3-b-glucoside was further explored for MD simulations. During the MD simulation study at 100 nanoseconds, a stable complex formation of AKT1 þ Peiminine and Imperialine-3-b-glucoside was observed. The binding free energy calculations using MM/GBSA showed significant binding of the ligand with protein (DG: −79.83±3.0kcal/mol) between AKT1 þ Peiminine was observed. The principal component analysis exhibited a stable converged structure by achieving global motion. Lastly, F. cirrhosa extracts also exhibited momentous anticancer activity through in vitro studies. Therefore, present study revealed the molecular mechanism of F. cirrhosa constituents for the effective treatment of BC by deactivating various multiple gene targets, multiple pathways particularly the PI3K-Akt signaling pathway. These findings emphasized the momentous anti-BC activity of F. cirrhosa constituents.
... We also explored its potential in other disease models. Tang et al. (2018) demonstrated peiminine's role as an adriamycin chemosensitizer in gastric cancer (Tang et al. 2018). Zhao et al. (2018) reported its inhibitory effects on glioblastoma growth through cell cycle arrest and autophagic flux (Zhao et al. 2018). ...
... We also explored its potential in other disease models. Tang et al. (2018) demonstrated peiminine's role as an adriamycin chemosensitizer in gastric cancer (Tang et al. 2018). Zhao et al. (2018) reported its inhibitory effects on glioblastoma growth through cell cycle arrest and autophagic flux (Zhao et al. 2018). ...
Ulcerative colitis is a chronic inflammatory disorder of the intestinal mucosa and a prevalent gastrointestinal condition in developed countries. Peiminine, derived from the Fritillaria imperialis plant, exhibits remarkable anti-inflammatory and anti-cancer properties. This study aims to investigate the anti-inflammatory effects of peiminine in an experimental model of ulcerative colitis. Ulcerative colitis was induced intra-rectally in all groups, except the negative control, using 100 μl of 4% acetic acid. Peiminine treatment was initiated after ulcerative colitis induction and symptom manifestation. After the final injection, mice were sacrificed on day 15 for assessment. Various parameters were evaluated, including disease activity index, myeloperoxidase activity, nitric oxide levels, production and expression of IL-1, IL-6, TNF-α cytokines, and expression of IL-1β, IL-6, TNF-α, iNOS, and COX2 genes. Microscopic pathological evaluation was performed on colon tissue. Peiminine treatment resulted in reduced levels of NO, MPO, IL-1β, IL-6, and TNF-α. Furthermore, the expression of IL-1β, IL-6, TNF-α genes, iNOS, and COX2 genes was decreased in response to peiminine treatment in these mice. This study demonstrates the effectiveness of peiminine in alleviating inflammatory manifestations and mitigating intestinal tissue damage in an experimental model of ulcerative colitis, probably by anti-inflammatory procedure. Peiminine holds potential as a therapeutic adjunct for the management of ulcerative colitis.
... Peiminine also decreases poly (ADP-ribose) polymerase (PARP) activity in hepatoma cells, and increases the expression of Bax, caspase-3, caspase-8, caspase-9, and cleaved PARP1, ultimately leading to apoptosis (Chao et al., 2019). It can also act as a chemosensitizer for doxorubicin in gastric cancer treatment by modulating the EGFR/FAK pathway (Tang et al., 2018). Peimine was also shown to induce cancer cell apoptosis by disrupting intracellular calcium homeostasis via the Ca 2+ /CaMKII/JNK pathway (Tan et al., 2020). ...
Fritillaria cirrhosa D. Don and F. thunbergii Miq. belong to the genus Fritillaria within the Liliaceae family. They are used in traditional Chinese medicines that are often administered in clinical settings as they have notable effects on cough, bronchitis, pneumonia, lung injury, cancer, and other diseases. In this review, we focus on the history, origin, similarities, and differences in efficacy, chemical composition, and pharmacological outcomes of the drugs obtained from F. cirrhosa (FRC) and F. thunbergii (FRT). We list various valuable pharmacological effects of FRC and FRT, including antitussive, expectorant, anti-inflammatory, antioxidant, and anticancer effects. Thus, this review offers a basis for the medical application of and further research into the pharmacological impacts of these two drugs. We believe that new drugs derived from the phytoconstituents of F. cirrhosa and F. thunbergii that have specific therapeutic properties can be developed in the future.
... As a natural compound extracted from Fritillaria thunbergii Bulbi, peiminine has been widely used as a traditional Chinese medicine to treat various diseases, including cancer [12,13] and atopic dermatitis [14]. Peiminine potentiates antioxidative [15], antiallergic [16] and anti-inflammatory [14] effects. ...
Myocardial infarction promotes cardiac remodeling and myocardial fibrosis, thus leading to cardiac dysfunction or heart failure. Peiminine has been regarded as a traditional anti-fibrotic Chinese medicine in pulmonary fibrosis. However, the role of peiminine in myocardial infarction-induced myocardial injury and fibrosis remained elusive. Firstly, rat model of myocardial infarction was established using ligation of the left coronary artery, which were then intraperitoneally injected with 2 or 5 mg/kg peiminine once a day for 4 weeks. Echocardiography and haemodynamic evaluation results showed that peiminine treatment reduced left ventricular end-diastolic pressure, and enhanced maximum rate of increase/decrease of left ventricle pressure (± dP/dt max) and left ventricular systolic pressure, which ameliorate the cardiac function. Secondly, myocardial infarction-induced myocardial injury and infarct size were also attenuated by peiminine. Moreover, peiminine inhibited myocardial infarction-induced increase of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α production, as well as the myocardial cell apoptosis, in the rats. Thirdly, peiminine also decreased the myocardial fibrosis related protein expression including collagen I and collagen III. Lastly, peiminine reduced the expression of p38 and phosphorylation of extracellular signal-regulated kinase 1/2 in rat model of myocardial infarction. In conclusion, peiminine has a cardioprotective effect against myocardial infarction-induced myocardial injury and fibrosis, which can be attributed to the inactivation of mitogen-activated protein kinase pathway.
... Numerous drugs exert their antitumor functions by inducing cell apoptosis (Sun et al., 2004;Hu and Xiao, 2015). Peiminine induces apoptosis through both extrinsic and intrinsic apoptotic pathways in liver cancer, represses proliferation and growth of colorectal carcinoma by inducing autophagic cell death, and serves as an adriamycin chemosensitizer via the EGFR/FAK pathway in gastric cancer (Lyu et al., 2015;Tang et al., 2018;Chao et al., 2019). Similarly, in this study, the rate of OS cell apoptosis was significantly increased after peiminine treatment. ...
Aims: Peiminine has been reported to have various pharmacological properties, including anticancer activity. In this study, we investigated the effect of this alkaloid on osteosarcoma and explored the underlying mechanisms.
Methods: To evaluate the antiosteosarcoma effects of peiminine in vitro, cell viability was assessed by CCK-8 and live/dead assays; the effects of the drug on apoptosis and the cell cycle were examined by flow cytometry; the effects on cell migration and invasion were detected by wound healing and Transwell assays, respectively, while its effects on autophagy were observed by transmission electron microscopy and an LC3 fluorescent puncta formation assay. The role of autophagy in the peiminine-mediated effects in osteosarcoma cells was evaluated by CCK-8 assay and western blotting after the application of the autophagy inhibitor chloroquine. The effect of peiminine on reactive oxygen species (ROS) production was analyzed using fluorescence confocal microscopy and spectrophotometry. Additionally, peiminine-treated osteosarcoma cells were exposed to SP600125, a JNK inhibitor, and N-acetylcysteine, a ROS scavenger, after which the contribution of the ROS/JNK signaling pathway to osteosarcoma was assessed using cell viability and LC3 fluorescent puncta formation assays, flow cytometry, and western blotting. A xenograft mouse model of osteosarcoma was generated to determine the antitumor effects of peiminine in vivo.
Results: Peiminine suppressed proliferation and metastasis and induced cell cycle arrest, apoptosis, and autophagy in osteosarcoma cells. These anticancer effects of peiminine were found to be dependent on intracellular ROS generation and activation of the JNK pathway. In line with these results, peiminine significantly inhibited xenograft tumor growth in vivo.
Conclusions: Peiminine induced G0/G1-phase arrest, apoptosis, and autophagy in human osteosarcoma cells via the ROS/JNK signaling pathway both in vitro and in vivo. Our study may provide an experimental basis for the evaluation of peiminine as an alternative drug for the treatment of osteosarcoma.
... 21,22 Through a searchable database, we found that in The Cancer Genome Atlas (TCGA) in the league has included information about EGFR somatic mutations, in human tumors, six mutation of EGFR have been proved in human cancers, their site distributed throughout the whole structure of EGFR gene mutation, both including the extracellular and intracellular domain of EGFR, indicating that EGFR mutations may be involved in the process of the whole signal to include with the combination of the ligands and the downstream signal transduction. 23,24 In the study of HCC, we have found that abnormal activation of EGF/EGFR signaling pathway is one of the key factors in the development of HCC. 25 In accordance with this, in the studies on the occurrence and development of EGFR polymorphism in liver cancer, rs4947986 polymorphism was highly correlated with the susceptibility to liver cancer. The study found that rs4947986 polymorphism was located 47 base from the boundary of exon 7, which was the key site for the dimerization of EGFR. ...
Background
Previous studies have shown that epidermal growth factor receptor (EGFR) promotes cell proliferation through the PI3K-Akt-mTOR signaling pathway and participates in the occurrence and development of hepatocellular carcinoma (HCC). Here, we focused on the functional polymorphism of EGFR in the 3ʹ-untranslated region (UTR), aiming to reveal the potential mechanisms by which functional polymorphism is associated with the risk and development of HCC in the Han Chinese population.
Methods
This study was a hospital-based case-control study. A total of 600 patients were enrolled, and another 600 healthy volunteers served as controls. The miR-associated SNPs in EGFR were screened, and genotyping was performed by TaqMan allele differential analysis. In this study, genotyping, real-time PCR, cell transfection and double luciferase reporter gene were used for subsequent analysis.
Results
HBV/HCV infection instead of alcohol exposure, smoking exposure, hypertension or diabetes mellitus was associated with an increased risk of HCC. Compared with TT genotypes, TG and GG genotypes of EGFR rs884225 were significantly associated with reduced HCC risk. The stratified analysis of association between rs884225 and HCC subgroup feature reveal a highly correlation with tumor size. Furthermore, qRT-PCR confirmed that EGFR rs884225, TG and GG genotypes were more likely to bind to miR-3196 and down-regulate EGFR level in cells, thereby inhibiting cell proliferation.
Conclusion
This study suggested that EGFR rs884225 is associated with a reduced risk of liver cancer and may be a developing biomarker.
... Adriamycin is a broad-spectrum anticancer drug that can intercalate DNA double strands to form stable complexes, thereby inhibiting DNA replication and RNA synthesis [4]. Nowadays, the mortality rate of breast cancer patient has been significantly reduced due to development of early detection methods and new drugs [5]. ...
Objective
We aimed to evaluate the therapeutic effects of paclitaxel in combination with mTOR inhibitor everolimus on adriamycin-resistant breast cancer cell line MDA-MB-231 (MDA-MB-231/ADR).
Materials and methods
MDA-MB-231/ADR cells were treated with different concentrations of paclitaxel and everolimus. The IC50 values after 48 h of treatment were measured by the MTT assay. The apoptosis rate and cell cycle were detected by flow cytometry. The protein expressions of Akt, PI3K, mTOR, p-pI3K, p-AKT and p-mTOR were detected by Western blot.
Results
When paclitaxel at ≥1.56 μg/ml was used, the growth of MDA-MB-231/ADR cells was inhibited more significantly than that of control group (P < 0.05). After treatment with ≥6.25 μg/ml everolimus, the cell growth was also suppressed more significantly (P < 0.05). The IC50 values of everolimus and paclitaxel were 32.50 μg/ml and 7.80 μg/ml, respectively. The inhibition rate of paclitaxel plus everolimus was significantly enhanced with increasing paclitaxel concentration (P < 0.001). After treatment with 7.80 μg/ml paclitaxel, the two drugs had best synergistic inhibitory effects on proliferation. Compared with drugs alone, the combination significantly promoted apoptosis (P < 0.001). The paclitaxel + everolimus group had significantly more cells in the G0-G1 phase than those of control and individual drug groups (P < 0.001). Everolimus significantly decreased mTOR and p-mTOR expressions compared with those of control group (P < 0.001). Compared with everolimus alone, the combination reduced the expressions more significantly (P < 0.05). Paclitaxel decreased the expression levels of PI3K, p-PI3K and p-AKT. Compared with paclitaxel alone, the combination significantly promoted the reduction of PI3K, p-PI3K and p-AKT expressions (P < 0.05).
Conclusion
Everolimus can enhance the effect of paclitaxel on MDA-MB-231/ADR cells, inhibit cell proliferation, induce apoptosis and arrest cell cycle in the G1 phase mainly by down-regulating the expressions of key proteins in the mTOR signaling pathway.
... Hence, to some extent, the above H-bonds enhanced the potential binding affinities of engleromycin, thereby interfering with or inhibiting the physiological activities of the two target enzymes. Doxorubicin could inhibit the malignant proliferation of tumor cells by interfering with the DNA's replication, transcription and synthesis, and have exhibited remarkable therapeutic effects on digestive tract cancers in clinic, including colorectal cancer, gastric cancer, esophageal cancer, etc. [36]. From this point, when docking into the same binding pocket in Top II with doxorubicin (Figure 2a), engleromycin might also interfere with the DNA biosynthesis during tumorigenesis. ...
Engleromyces goetzei P. Henn. (E. goetzei) has been widely used as a traditional herb for many years in Kenya due to its diverse biological effects. Although engleromycin was first isolated from E. goetzei in 1980, its pharmacological activity is still unknown. In this study, engleromycin from E. goetzei was identified by spectroscopic analyses, and subsequently examined for its antiproliferative activity using human cancer cell lines of SGC-7901, HT-29, HeLa and A549. As a result, it was revealed that engleromycin strongly inhibited the growth of SGC-7901, HT-29, HeLa and A549 cells with IC50 values at 26.77 ± 1.69 µM, 7.73 ± 0.18 µM, 7.00 ± 0.12 µM and 3.14 ± 0.03 µM, respectively. The results of topoisomerase II (Top II) inhibition assay in vitro implied that engleromycin might be a Top II inhibitor. Further insights into the potential mechanism of antiproliferative activity displayed that engleromycin could dock into the binding pockets of Top II, like the clinical inhibitor doxorubicin, and then inhibit the biological activity of Top II. Taken together, our findings suggest that engleromycin has an anticancer potential, and may serve as a leading compound for the development of antitumor agents.
... Peimine and peiminine are isosteroidal alkaloids and the major biological active constituents of FU and FT (Figure 1) [6]. Various pharmacological effects of peimine and peiminine have been reported [7], such as anti-inflammatory [6,8], anti-tumor [9][10][11], antioxidant [12], antitussive, and sedative [13] effects. Peimine inhibits the production of pro-inflammatory cytokines, such as IL-6, IL-8, and TNF-α. ...
A simple and high sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of peimine and peiminine in beagle dog plasma after the oral administration of Fritillariae ussuriensis Maxim and Fritillariae thunbergii Miq powder. Chromatographic separation was achieved on an ACQUIT UPLC® BEH C18 column (1.7 μm, 2.1 × 100 mm) in a gradient elution way with a mobile phase consisting of acetonitrile and water containing 0.1% formic acid at a flow rate of 0.4 mL/min. The plasma samples were prepared by a liquid–liquid extraction (LLE) method with ethyl acetate. The analytes were detected with a triple quadrupole tandem mass spectrometry (MS) in multiple reaction monitoring (MRM) mode and a positive ion electrospray ionization (ESI) of the transitions at m/z 432.4→414.4 for peimine and m/z 430.3→412.3 for peiminine. The method was linear for two analytes over the investigated range with all determined correlation coefficients exceeding 0.9900. The lower limit of quantification (LLOQ) was 0.988 ng/mL for peimine and 0.980 ng/mL for peiminine. The mean extraction recoveries of peimine and peiminine at three quality control samples (QC) levels were ranged from 82.56 to 88.71%, and matrix effects ranged from 92.06 to 101.2%. The intra-day and inter-day precision and accuracy were within the acceptable limits at LLOQ and QC levels. The method was effectively and successfully applied to the pharmacokinetics of peimine and peiminine after oral administration of powder to beagle dogs. The obtained results may be help to guide the clinical application of Fritillaria ussuriensis Maxim and Fritillaria thunbergii Miq.
... The anti-cancer activity of (S)-crizotinib was investigated using two human GC cell lines, SGC-7901 and BGC-823, in which the RTKs have been reported to be highly activated. 12,13 (S)-crizotinib decreased viability of both cell lines at comparable levels (IC 50 = 21.33 and 24.81 μM, respectively) (Fig. 1a), a finding consistent with cell rounding and decreased cell density ( Figure S1). The effects of (S)-crizotinib on apoptosis of the GC cells were determined with annexin V/PI staining and detection by flow cytometry. ...
Gastric cancer (GC), a common gastrointestinal malignancy worldwide, has poor prognosis and frequent recurrence. There is a great need to identify effective therapy for GC. Crizotinib is a multi-targeted, clinically available oral tyrosine kinase inhibitor approved for lung cancer, but its use for the highly heterogeneous disease of GC is unknown. The goal of this study was to investigate the anti-cancer mechanisms of the (S)-crizotinib in inhibiting GC growth. Human GC cell lines (SGC-7901 and BGC-823) and the (S)-crizotinib-resistant BGC-823/R were cultured for determining the effects of (S)-crizotinib on cell viability, apoptosis, oxidant generation, and cell cycle progression. Involvement of ROS, Akt signaling, MTH1, and DNA damage was tested with respective pharmacological blockade. The in vivo anti-tumor effects of (S)-crizotinib were determined using xenograft tumor mice. Results indicated that (S)-crizotinib decreased GC cell viability, induced growth arrest and apoptosis, and increased levels of γH2AX and Ser1981-phosphorylated ATM, which were inhibited by NAC. The anti-cancer mechanism of (S)-crizotinib was independent of MTH1. Moreover, ATM-activated Akt, a pro-survival signal, whose inhibition further enhanced (S)-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice, and re-sensitized resistant GC cells to (S)-crizotinib. (S)-crizotinib reduced GC cell and tumor growth through oxidative DNA damage mechanism and triggered pro-survival Akt signaling. We conclude that inclusion of Akt inhibition (to block the survival signaling) with (S)-crizotinib may provide an effective and novel combination therapy for GC in the clinical setting.
