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In silico identification of natural products from Traditional Chinese Medicine for cancer immunotherapy.
Cai, C, Wu, Q, Hong, H, He, L, Liu, Z, Gu, Y, Zhang, S, Wang, Q, Fan, X, Fang, J
Scientific reports. 2021;(1):3332
Abstract
Advances in immunotherapy have revolutionized treatments in many types of cancer. Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant application against cancer, is emerging as an important medical resource for developing innovative cancer treatments, including immunotherapy. In this study, we developed a quantitative and systems pharmacology-based framework to identify TCM-derived natural products for cancer immunotherapy. Specifically, we integrated 381 cancer immune response-related genes and a compound-target interaction network connecting 3273 proteins and 766 natural products from 66 cancer-related herbs based on literature-mining. Via systems pharmacology-based prediction, we uncovered 182 TCM-derived natural products having potential anti-tumor immune responses effect. Importantly, 32 of the 49 most promising natural products (success rate = 65.31%) are validated by multiple evidence, including published experimental data from clinical studies, in vitro and in vivo assays. We further identified the mechanism-of-action of TCM in cancer immunotherapy using network-based functional enrichment analysis. We showcased that three typical natural products (baicalin, wogonin, and oroxylin A) in Huangqin (Scutellaria baicalensis Georgi) potentially overcome resistance of known oncology agents by regulating tumor immunosuppressive microenvironments. In summary, this study offers a novel and effective systems pharmacology infrastructure for potential cancer immunotherapeutic development by exploiting the medical wealth of natural products in TCM.
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Tetrandrine inhibits colon carcinoma HT-29 cells growth via the Bcl-2/Caspase 3/PARP pathway and G1/S phase.
Li, J, Wang, Q, Wang, Z, Cui, N, Yang, B, Niu, W, Kuang, H
Bioscience reports. 2019;(5)
Abstract
Tetrandrine (Tet) bisbenzylisoquinoline alkaloids isolated from Stephania tetrandra and other related species of Menispermaceae. It has been demonstrated to have positive therapeutic effects on cardiovascular disease, hypertension, silicosis, autoimmune diseases. In recent years, some reports have shown that Tet has anticancer activity in human cancers. To explore the pharmacological activity and mechanism of Tet on colon cancer and its unique advantages as a natural product. In the present study, analyses of the cell cycle, apoptosis, targets prediction, molecular docking, and alterations in protein levels were performed to elucidate how Tet functions in colon cancer. We found that Tet robustly induced arrest at the G1 phase in colon cancer cell line HT-29. It induced HT-29 cell apoptosis in a dose-dependent manner. Similarly, analysis of protein expression levels in HT-29 cells showed down-regulation of Bcl-2, pro-caspase 3, pro-caspase 8, PARP, cyclin D1 (CCND1), cyclin-dependent kinase 4 (CDK 4), and up-regulation of Bax, active caspase 3, and active caspase 8. These results indicate that Tet induces apoptosis of colon cancer cells through the mitochondrial pathway and caspase family pathway. Molecular docking showed interaction effects and binding energy. Comparing with the CDK4 inhibitors ribociclib and palbociclib, the docking energy is similar to the docked amino acid residues. Therefore, we conclude that Tet and the CCND1/CDK4 compound could form hydrogen bonds and a stable compound structure, which can inhibit colon cancer cells proliferation by regulating CCND1/CDK4 compound and its downstream proteins phosphorylated Rb (p-Rb). In summary, Tet may be a potential drug for colon cancer therapy.
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Growth inhibition and induction of apoptosis and differentiation of tanshinone IIA in human glioma cells.
Wang, J, Wang, X, Jiang, S, Yuan, S, Lin, P, Zhang, J, Lu, Y, Wang, Q, Xiong, Z, Wu, Y, et al
Journal of neuro-oncology. 2007;(1):11-21
Abstract
Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen, a widely used Chinese herbal medicine. It has antioxidant properties, cytotoxic activities against multiple human cancer cells, inducing apoptosis and differentiation of some human cancer cells. The purpose of this study is to confirm its anticancer activity on human glioma cells, and to elucidate mechanism of its activity. Human glioma cells were tested in vitro for cytotoxicity, colony formation inhibition, BrdU incorporation after treatment with tanshinone IIA. Its effect of apoptosis induction was detected through EB/AO staining, cell cycle analysis and the expressions of ADPRTL1 and CYP1A1 genes, the differentiation induction effect was investigated through morphology, mRNA and protein expressions of GFAP and nestin genes by RT-PCR and immunocytochemistry. Tanshinone IIA demonstrated a dose- and time-dependent inhibitory effect on cell growth, IC(50) was 100 ng/ml, and it significantly inhibited colony formation and BrdU incorporation of human glioma cells. After treatment with 25-100 ng/ml of tanshinone IIA, the apoptotic cells increased significantly (P < 0.01), the cells in G(0)/G(1) phase increased (P < 0.01), and decreased in S phase, ADPRTL1 and CYP1A1 mRNA expression increased 1-2 folds. The cells treated with 100 ng/ml tanshinone IIA demonstrated astrocytes or neuron-like morphology, GFAP mRNA and protein expressions increased, nestin mRNA and protein expressions decreased significantly. The findings in this study suggested that tanshinone IIA exhibited strong effects on growth inhibition and induction of apoptosis and differentiation in human glioma cells. It might serve as a novel promising differentiation-inducing and/or therapeutic agent for human gliomas, and need to be investigated further.
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VP-16 resistance in the NCI-H460 human lung cancer cell line is significantly associated with glucose-regulated protein78 (GRP78) induction.
Wang, Q, Wang, T, Wang, Y, Wang, W, Wang, Y, Hu, X, Shao, S, Zhang, J, Suo, Z
Anticancer research. 2007;(4B):2359-64
Abstract
AIM: To investigate the relationship between the expression of glucose-regulated protein (GRP78) and resistance to VP-16 in the NCI-H460 cell line. METHODS RT-PCR, real-time RT-PCR and Western blotting were used in analyzing the expression of GRP78 at mRNA and protein levels in the NCI-H460 cell line induced by A23187 at different concentrations. Cell survival with VP-16 was determined using a colony-formation assay with the account of IC50. RESULTS The expression of GRP78 at both the mRNA and protein levels was higher in the NCI-H460 cell line induced by A23187. A23187 treatment resulted in up to 4.8-fold elevation of GRP78 mRNA and up to 3.2-fold elevation of GRP78 protein in the experimental cells compared to the controls, all in a dose-dependent manner. The IC50s for VP-16 in the cells pretreated with different concentrations of A23187 (0, 1, 2, 4 and 6 microM) were: 12.11 +/- 0.83, 12.68 +/- 1.04, 25.82 +/- 1.83, 37.46 +/- 1.89 and 45.19 +/- 2.34 microM, respectively. Compared to the control, there was a significant elevation of IC50 for VP-16 in the cells pretreated with A23187. Survival curve analysis also showed that the induction of A23187 caused a significantly longer survival for the cells subjected to VP-16 treatment (p < 0.05). CONCLUSION A23187 treatment is highly effective for the induction of GRP78 and subsequent development of resistance to VP-16 in the human lung cancer NCI-H460 cell line. Based on the trend of the change in IC50 and the expression of GRP78 in differently exposed cells, we conclude that the induction of GRP78 by A23187 is significantly associated with the resistance to VP-16.