Oridonin induces growth inhibition and apoptosis in human gastric carcinoma cells by enhancement of p53 expression and function

Bi, Enxu; Liu, Dengqiang; Li, Youxi; Mao, Xuying; Wang, Aihua; Wang, Jingtao

doi:10.1590/1414-431x20187599

Cited by 19 publications

(14 citation statements)

References 34 publications

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“…On the other hand, expression of p21 cip1/waf1 and DR5 was significantly increased in bortezomib-treated cells even without noticeable change in p53 at early time point. Oridonin, a herbal diterpenoid, increased expression of p53 and Bax in SNU-216 cells, demonstrating its inducibility and functionality in the cells 29. Therefore, it is conceivable that bortezomib might activate an alternative signaling pathway that obviates p53 induction to upregulate DR5 and p21 cip1/waf1 expression.…”

Section: Discussionmentioning

confidence: 99%

Synergistic apoptosis of human gastric cancer cells by bortezomib and TRAIL

Bui

et al. 2019

Int. J. Med. Sci.

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Resistance against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death of cancer cells is a major obstacle in clinical application of TRAIL. Variable response to TRAIL of gastric cancer cells, synergy of TRAIL with bortezomib and potential mechanisms behind the phenomena were investigated in this study. The response to TRAIL varied among six gastric cancer cell lines, which correlated with the expression of apoptotic TRAIL receptors. Analysis of TCGA gene expression data showed that DR4 expression correlated with DR5 in gastric cancer. Although higher expression of DR4 was significantly associated with lower T, N and TNM stages, neither DR4 nor DR5 expression meaningfully influenced overall survival rate. Combined treatment of TRAIL with bortezomib resulted in strong synergistic response with enhanced activation of caspases-8,-9 and-3, and increased Annexin V-binding cell fractions in TRAIL-resistant SNU-216 cells. Bortezomib increased the expression of p21 cip1/waf1 , but p21 cip1/waf1 silencing did not restore cell viability significantly. Bortezomib also increased DR5 expression and knockdown of DR5 expression significantly recovered cell viability reduced by the combination treatment. Bortezomib decreased phosphorylation of ERK1/2, but increased that of JNK. Treatment with either an ERK1/2 inhibitor U0126 or a JNK inhibitor SP600125 rescued SNU-216 from dying of bortezomib or combined treatment. However, upregulation of DR5 by bortezomib was knocked down only by inhibition of ERK1/2 activation significantly, but not by JNK activity inhibition. In summary, upregulation of DR5 by bortezomib is of critical significance in the synergy of bortezomib with TRAIL in apoptosis of TRAIL-resistant SNU-216 and that activity of ERK1/2 is required in the bortezomib-induced DR5 overexpression.

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Section: Discussionmentioning

confidence: 99%

Synergistic apoptosis of human gastric cancer cells by bortezomib and TRAIL

Bui

et al. 2019

Int. J. Med. Sci.

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“…Epidermal growth factor receptor (EGFR) is a glycoprotein that plays an important role in physiological processes such as proliferation, apoptosis and differentiation of cell by activating the calcium signaling pathway, MAPK signaling pathway and PI3K/AKT signaling pathway ( Carlisle et al., 2007 ). As an important anticancer gene, the inactivation of p53 plays an important role in tumor formation, and increasing studies have found that the p53 plays a crucial role in retarding tumor cell cycle, promoting tumor cell apoptosis and inhibiting tumor angiogenesis ( Bi et al., 2018 ; Li P. et al., 2019 ; Wang et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Investigate the Anticancer Mechanism and Potential Active Ingredients of Rheum palmatum L. Against Lung Cancer via Induction of Apoptosis

Zhang

Liu

et al. 2020

Front. Pharmacol.

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Rheum palmatum L. (RPL) is a known traditional herbal medicine with the functions of “ heat-clearing and damp-drying ” in traditional Chinese medicine. Its anti-cancer effect against lung cancer has been confirmed previously, but the related mechanisms and active substances for its action has been little studied. This study adopted the network pharmacology, built the network map of drug ingredients and disease targets (DDN), and discussed the effective components of RPL and its possible mechanisms. All constituents of RPL were collected through database search and literature mining, and the potential active constituents were screened. The inverse pharmacophore matching model was used to predict the targets of active ingredients, and the method was supplemented by database retrieval and literature mining. Compounds-target data were inputted into Cytoscape software to build the DDN of RPL, and functional annotation analysis and pathway enrichment analysis were carried out. Finally, 20 active compounds were screened, which acted on 817 targets. A total of 22,418 lung cancer-related targets were collected, and 761 overlapped with drug targets. By bioinformatics annotation of these overlapping genes, a total of 235 gene ontology (GO) functional annotation analyses and 46 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were obtained. It was found that the enrichment of GO and KEGG was associated with apoptosis, suggesting RPL plays an anti-lung cancer role via inducing cell apoptosis. Subsequent cell experiment results showed RPL and its active constituents inhibited the proliferation of A549 cells and reduced clone formation rate of A549 cells via induction of apoptosis. In this study, the pharmacodynamic basis and mechanism of RPL against lung cancer were studied from the perspective of systematic pharmacology, which would be beneficial for further elucidating the anticancer effect of RPL on lung cancer.

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“…It was observed that the change of TP53 mRNA level was not the reason for the enhanced expression of p53 in NB cells. And, this finding is inconsistent with a previous report in gastric cancer cells . This may be due to the fact that cells of different origins respond differently to oridonin: gastric cancer cells originate from epithelial cells and NB cells originate from neural crest.…”

Section: Discussionmentioning

confidence: 99%

“…And, this finding is inconsistent with a previous report in gastric cancer cells. 22 This may be due to the fact that cells of different origins respond differently to oridonin: gastric cancer cells originate from epithelial cells and NB cells originate from neural crest. Mdm2 is the major negative regulator of p53, for it can promote the degradation of p53 by increasing its ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19][20] It is especially crucial that several studies have shown that during the apoptosis of cancer cells induced by oridonin or its derivatives, p53 is reactivated and the proteins on the downstream of p53 are also altered. 20,21 For example, oridonin induces the growth inhibition and apoptosis of gastric cancer cells by regulating the expression and function of p53 22 ; the anticancer effects of oridonin on colon cancer cells are mediated through BMP7/ p38 MAPK/p53 signaling pathway 23 ; Geridonin, a derivative of oridonin, in combination with paclitaxel can lead to the accumulation of p53, and further apoptosis of gastric cancer cells by the mitochondrial pathway. 24 Furthermore, the apoptosis and autophagy of murine fibrosarcoma cells induced by oridonin are also p53-dependent.…”

Section: Introductionmentioning

confidence: 99%

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Oridonin induces Mdm2‐p60 to promote p53‐mediated apoptosis and cell cycle arrest in neuroblastoma

et al. 2019

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Oridonin could induce NB (neuroblastoma) cells growth inhibition by inducing apoptosis and cell cycle arrest, and the molecular mechanisms behind the effects deserve to be further explored. Here, oridonin was confirmed to cause the reactivation of p53 (cellular tumor antigen p53) to promote the expression of a series of apoptosis‐ and cell cycle arrest‐related proteins for the biological effects. During the process, oridonin relied on the caspase activation to cleave p53‐induced Mdm2 (E3 ubiquitin‐protein ligase Mdm2) to generate Mdm2‐p60. The generation of Mdm2‐p60 stabilized p53, and resulted in p53 accumulation for p53 continuous activation. In our research, it was also found that the reactivation of p53 induced by oridonin was closely related with the generation of ROS (reactive oxygen species). Taken together, these findings explain that oridonin exerts its anticancer activity partially by targeting the Mdm2‐p53 axis in NB cells, which lay an experimental base for future research of exploring the effects and molecular mechanisms of oridonin.

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Oridonin induces growth inhibition and apoptosis in human gastric carcinoma cells by enhancement of p53 expression and function

Cited by 19 publications

References 34 publications

Synergistic apoptosis of human gastric cancer cells by bortezomib and TRAIL

Synergistic apoptosis of human gastric cancer cells by bortezomib and TRAIL

A Network Pharmacology Approach to Investigate the Anticancer Mechanism and Potential Active Ingredients of Rheum palmatum L. Against Lung Cancer via Induction of Apoptosis

Oridonin induces Mdm2‐p60 to promote p53‐mediated apoptosis and cell cycle arrest in neuroblastoma

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