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Investigation of Inhibition Effect of Gossypol-Acetic Acid on Gastric Cancer Cells Based on a Network Pharmacology Approach and Experimental Validation.
Liu, Y, Ma, Y, Li, Z, Yang, Y, Yu, B, Zhang, Z, Wang, G
Drug design, development and therapy. 2020;:3615-3623
Abstract
BACKGROUND Gastric cancer (GC) is one of the major public health problems worldwide with high morbidity and mortality. Nowadays, traditional medicine may hold promise for the treatment of cancers. Gossypol-acetic acid (GAA) is a male contraceptive agent that shows anti-tumor effects on multiple types of cancers. However, whether GAA would inhibit the progression of GC remained unclear. METHODS The potential targets of GAA were predicted by the Pharmmapper software and GC-related genes were obtained from the GeneCard database. The "GC-targets-GAA" network was constructed using the Cytoscape software. The PPI analysis of intersection genes was performed using the String software. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the DAVID software to explore the potential mechanism underlying the regulatory role of GAA in GC. The MTS test, plate cloning test, cell cycle and apoptosis assays were used to verify the function of GAA in GC. RESULTS Ten hub genes related to cell cycle progression and apoptosis were identified. Many cancer-related signaling pathways were visualized by the Cytoscape software. Among them, the PI3K-Akt signaling pathway was the highest-ranked pathway. The MTS test and plate cloning test showed that GAA inhibited the proliferation of GC cells. The cell cycle and apoptosis assays showed that GAA induced G1 phase cell cycle arrest and apoptosis in GC cells. CONCLUSION Our study demonstrated the anti-tumor effect of GAA on GC through multiple targets and signaling pathways. These results provided a theoretical basis for further investigation of GAA in preclinical and clinical studies, and suggested the potential use of GAA as a novel therapeutic agent for the treatment of GC.
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Phytochemicals of garlic: Promising candidates for cancer therapy.
Zhang, Y, Liu, X, Ruan, J, Zhuang, X, Zhang, X, Li, Z
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2020;:109730
Abstract
Of the numerous health benefits of garlic, the anticancer effect is probably the most noticeable. Observations over the past years have shown that the consumption of garlic in the diet provides strong protection against cancer risk. Previous studies involving garlic phytochemicals have usually focused on the cancer chemopreventive properties, but there is little published evidence showing its therapeutic potential in cancer treatment. In view of the multitargeted carcinoma actions and lack of severe toxicity, some components of garlic are likely to play vital roles in the selective killing of cancer cells. However, the rational design of experimental studies and clinical trials are required to verify this concept. This paper discusses the promises and pitfalls of garlic for the treatment of cancer.
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Inhibition of SOX15 Sensitizes Esophageal Squamous Carcinoma Cells to Paclitaxel.
Zhang, M, Wang, J, Gao, T, Chen, X, Xu, Y, Yu, X, Guo, X, Zhuang, R, Li, Z, Wu, H, et al
Current molecular medicine. 2019;(5):349-356
Abstract
BACKGROUND SOX15 is a crucial transcription factor involved in the regulation of embryonic development and in the cell fate determination. It is also an important mediator of tumorigenesis in cancer. METHODS Here, we sought to explore the expression patterns and biological functions of SOX15 in esophageal squamous cell carcinomas (ESCC). SOX15 was found aberrantly overexpressed in ESCC tumors. RESULTS Experimentally, inhibition of SOX15 through RNAi suppressed cell proliferation in ESCC cells and sensitized cancer cells to paclitaxel, but not to Cisplatin. Moreover, inhibition of SOX15 significantly repressed the expression of genes associated with WNT and NOTCH signaling pathways, which may contribute to the increased sensitivity to paclitaxel. CONCLUSION In conclusion, the current study revealed that inhibition of SOX15 in ESCC cells sensitizes the ESCC cells to paclitaxel, suggesting that the SOX15 expression level may predict the therapeutic outcomes for paclitaxel treatment for ESCC.
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Dose-response modeling of etoposide-induced DNA damage response.
Li, Z, Sun, B, Clewell, RA, Adeleye, Y, Andersen, ME, Zhang, Q
Toxicological sciences : an official journal of the Society of Toxicology. 2014;(2):371-84
Abstract
The 2007 National Research Council Report "Toxicity Testing in the 21st Century: A Vision and A Strategy" recommended an integrated, toxicity pathway-oriented approach for chemical testing. As an integral component of the recommendation, computational dose-response modeling of toxicity pathways promises to provide mechanistic interpretation and prediction of adverse cellular outcomes. Among the many toxicity pathways, the DNA damage response is better characterized and thus more suited for computational modeling. In the present study, we formulated a minimal mathematical model of this pathway to examine the dose response for etoposide (ETP), an anticancer drug that causes DNA double strand breaks (DSBs). In the model, DSB results from inhibition of topoisomerase by ETP and p53 is activated by a bistable switch composed of a positive feedback loop between ATM and γH2AX. Our stochastic model recapitulated the dose response for several molecular biomarkers measured with flow cytometry in HT1080 cells, including phosphorylated p53, ATM, γH2AX, and micronuclei. Model simulations were consistent with a bimodal pattern of p53 activation and a graded population-averaged response at high ETP concentrations. The graded response was a result of heterogeneous activation of individual cells due to molecular stochasticity. This work shows the value of combining data collection on single cell responses and mechanistic, stochastic modeling to develop and test hypothesis for the circuitry of important toxicity pathways. Future studies will determine how well this initial modeling effort agrees with a broader set of experimental studies on pathway responses by examining a more diverse group of DNA-damaging compounds.
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Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro.
Zhang, Y, Kong, C, Zeng, Y, Wang, L, Li, Z, Wang, H, Xu, C, Sun, Y
Molecular carcinogenesis. 2010;(4):374-85
Abstract
Ursolic acid (UA), a pentacyclic triterpenoid compound, has been demonstrated to have an antiproliferative effect in various tumors. We investigated the cell killing effects of UA in the human hormone refractory prostate cancer cell line, PC-3 cells. Also, the molecular mechanisms underlying its antigrowth effect were explored. We found that UA treatment in vitro can effectively inhibit PC-3 cell viability in a dose-dependent manner by inducing apoptosis, demonstrated by annexin V-FITC/propidium iodide staining. Both extrinsic and intrinsic apoptotic pathways appear to be triggered by UA treatment, because inhibiting activation of both caspase-8 and -9 could prevent UA-induced apoptosis in PC-3 cells. The c-Jun N-terminal kinase (JNK) was found to be activated, followed by Bcl-2 phosphorylation and activation of caspase-9. On the other hand, UA inhibited the Akt pathway, subsequently upregulating the expression of Fas ligand (FasL), which initiates death receptor-mediated apoptosis in PC-3 cells. Importantly, experimentally lowering FasL expression by siRNA significantly inhibited UA-induced caspase-8 activation and at least partly attenuated the consequent apoptosis, suggesting an involvement of FasL and its regulating pathway in the cell killing effect of UA. UA also inhibited cell invasion by downregulating matrix metalloproteinase-9 via inhibition of Akt in PC-3 cells. Although further evaluation of the UA effects in vivo is needed, the present results suggest the potential utility of UA as a novel therapeutic agent in advanced prostate cancer.