Cisplatin (DDP) is a potent and widely applied chemotherapeutic agent. However, its clinical efficacy for the treatment of liver cancer is limited by adverse effects and the development of resistance. Combinatorial therapy may alleviate these issues. Dihydroartemisinin (DHA) is a first-generation derivative of artemisinin. The effects of DDP on liver cancer when applied in combination with DHA have not previously been studied. Therefore, the present study aimed to investigate the effects of DHA combined with DDP on HepG2 cells and their potential underlying molecular mechanisms. HepG2 cells were treated with different concentrations of DHA and/or DDP. Cell Counting Kit-8 assay was used to assess the cell viability. Cell proliferation and apoptosis were quantified using flow cytometry, acridine orange/ethidium bromide (AO/EB) fluorescent dual staining and the colony formation assay. Cell migration was quantified using the Transwell and wound healing assays. The HepG2 cell protein expression levels of Fas, Fas-associated death domain (FADD), procaspase-3, cleaved caspase-3, pro-caspase-8, cleaved caspase-8, Bax, Bcl-2, E-cadherin and N-cadherin, were detected via western blotting. Gelatin zymography was used to assess the levels of MMP-9 secreted by HepG2 cells into the supernatant. Following combined DHA and DDP treatment, the percentage of apoptotic cells was significantly increased, whereas cell proliferation and migration were significantly reduced, compared with cells treated with DDP only. DHA and DPP in combination significantly inhibited the expression of MMP-9, significantly increased the protein expression levels of Fas, FADD, Bax and E-cadherin, significantly increased the ratio of cleaved caspase-3 and cleaved caspase-8 to their precursor proteins and significantly decreased the protein expression levels of Bcl-2 and N-cadherin. The findings of the present study suggested that, DHA may confer synergistic effects with DDP in potentially promoting apoptosis and inhibiting the epithelial-mesenchymal transition for the treatment of liver cancer.
Anemone flaccida Fr. Schmidt, a Traditional chinese Medicine, has been used in the treatment of rheumatoid arthritis (RA) for numerous years. However, the specific mechanisms remain to be elucidated. Thus, the present study aimed to investigate the main chemical constituents and potential mechanisms of Anemone flaccida Fr. Schmidt. The ethanol extract obtained from Anemone flaccida Fr. Schmidt (eaF) was analyzed using mass spectrometry to determine the main components and the therapeutic effects of eaF on RA were verified using a collagen-induced arthritis (CIA) rat model. results of the present study demonstrated that synovial hyperplasia and pannus of the model rats were significantly improved following eaF treatment. Moreover, the protein expression levels of VeGF and cd31-labeled neovascularization were significantly reduced in the synovium of CIA rats following treatment with eaF, compared with those of the untreated model group. Subsequently, in vitro experiments were carried out to verify the impact of eaF on synovial proliferation and angiogenesis. results of the western blot analysis revealed that eaF inhibited the Pi3K signaling pathway in endothelial cells, which is associated with anti-angiogenesis. in conclusion, results of the present study demonstrated the therapeutic effects of Anemone flaccida Fr. Schmidt on ra and preliminarily revealed the mechanisms of this drug in the treatment of ra.
Background: Zuojinwan (ZJW), a famous Chinese medicine formula, has been widely used to treat gastric cancer (GC) which is the third leading cause of cancer-related death around the world.miR-107, a kind of small non-coding RNAs, play a vital role in the occurrence and development of GC. Aim:A network pharmacology-based strategy combined with in vitro and in vivo experiment were employed to investigate the anticancer effect, potential targets, and molecular mechanism of ZJW against GC by miR-107. Methods:Potential targets and signaling pathways of ZJW to treating gastric cancerby miR-107 were determined usingbioinformatics analysis from public databases. miR-107 and its downstream protein expression levels in GC tissues and cell lines were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) or western blot,which were further confirmed by Luciferase reporter assay and Pearson correlation test.The anticancer effect of ZJW in vitro and in vivo were examined by Nude mouse xenograft tumor model and MGC-803 cells. The possible antitumor mechanism of ZJW was studied by using western blot analysis. Results:A total of 33 bioactive ingredients and 147 gene targets of ZJW acting on GC by miR-107 were identified. The miR-107 level was reduced and RUNX1T1 was down-expressed in GC samples.The expression of target was positively correlated with miR-107 in patients with GC.RUNX1T1 was targeted by miR-107.Since overexpression of miR-107 significantly decreased RUNX1T1 expression in MGC-803 cells, and knockdown of miR-107 enhanced RUNX1T1 expression. ZJW inhibited MGC-803 cells proliferation in dose- and time-dependent manner by activating PI3K/AKT/mTOR pathway and arresting the cell cycle in S phase through regulating the expression of Cyclin A, Cyclin B1 and Cyclin E. ZJW suppressed MGC-803 cells migration in dose-dependent manner by increasing E-cadherin expression. ZJW induced MGC-803 cells apoptosis by Fas death receptor and Bcl-2/Bax pathway. Tumor growth was attenuated by ZJW in nude mouse.miR-107 expression was downregulated in ZJW-treated group compared with untreated group, while the protein expression of RUNX1T1 was upregulated. Conclusions: showed significant anti-tumor activity against gastric cancer MGC-803 cells through multiple signaling pathways via miR-107/RUNX1T1 axis both in vitro and in vivo.
Purpose Dihydroartemisinin (DHA), a derivative of artemisinin that is well-known as an antimalarial drug, has been reported to have anti-tumor and anti-angiogenesis effects. However, whether and how it inhibits angiogenesis in breast cancer is poorly understood. In this study, we detected the anti-angiogenesis effect of DHA on breast cancer. Methods Firstly, we detect the anti-angiogenesis effect of DHA on breast cancer in a chick chorioallantois membrane model. Then, we collected the conditioned medium of MDA-MB-231cells used in aortic ring angiogenesis assay, and HUVECs migration and tube formation assay. Finally, we used gelatin zymography, cellular immunofluorescence assay and western blot analysis to study signaling modulators regulated by DHA in MDA-MB-231 cells. Results The results showed that angiogenesis induced by MDA-MB-231 cells was attenuated by DHA. Vessel sprout and tube-formation of vascular endothelial cells were also depressed when cultured with CM from MDA-MB-231 pretreated with DHA. What’s more, the expression, and activities of matrix metalloproteinase 2 and 9 (MMP-2/-9) in MDA-MB-231 cells were downregulated by DHA. Further studies showed that DHA downregulated the expression of p-PI3K, p-AKT, p-ERK, and p-NF-κB proteins in tumor cells. Conclusion DHA was highly efficacious in inhibiting angiogenesis induced by breast cancer cells. The downregulating of MMP-2/9 through inhibiting phosphorylation of PI3K, AKT, and ERK in tumor cells may be the key factors in the inhibitory effect of DHA on angiogenesis.
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