Triptolide inhibits tumor growth by induction of cellular senescence

Li, Ruidong; Zhang, Xiaofei; Tian, Xiaoying; Shen, Chen; Zhang, Quanbao; Zhang, Yihong; Wang, Zhengxin; Wang, Feifei; Tao, Yue

doi:10.3892/or.2016.5258

Cited by 20 publications

(18 citation statements)

References 31 publications

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“…It was reported that triptolide induced cell cycle arrest in HepG2 cells at relatively lower concentrations. Inconsistent with this study [ 18 , 19 ], the cell cycle distribution in liver cancer cells was not significantly altered in the presence of triptolide (Additional file 3 : Figure S1A and B). In addition, the expression of other key cell cycle regulators, such as cyclin A, cyclinD, and Rb showed no significant alterations after incubation with triptolide (Additional file 3 : Figure S1C).…”

Section: Resultssupporting

confidence: 79%

C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells

Shi

Yuan

et al. 2018

J Exp Clin Cancer Res

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BackgroundTriptolide is a structurally unique diterpene triepoxide with potent antitumor activity. However,the effect and mechanism of triptolide on hepatocellular carcinoma (HCC) is not well studied.MethodsCells were treated with triptolide, and the anti-HCC activity of triptolide was evaluated using flow cytometry, western blot, and xenograft studies. MicroRNA microarray and quantitative reverse-transcription polymerase chain reaction was used to identify differential microRNAs induced by triptolide. Chromatin immunoprecipitation assay was employed to study the interaction between c-Myc and genomic regions of miR106b-25. MicroRNAs overexpression and knockdown experiments were performed to determine the role of these microRNAs in triptolide-induced apoptosis.ResultsTriptolide inhibited cell proliferation and induced marked apoptosis in multiple HCC cell lines with different p53 status. Several signaling molecules involved in different pathways were altered after the treatment of triptolide. Xenograft tumor volume was significantly reduced in triptolide-treated group compared with vehicle control group. Two miRNA clusters, miR-17-92 and miR-106b-25, were significantly suppressed by triptolide, which resulted in the upregulation of their common target genes, including BIM, PTEN, and p21. In HCC samples, high levels of these miRNA clusters correlated with shorter recurrence free survival. Triptolide inhibited the expression of theses miRNAs in a c-Myc-dependent manner, which enhanced triptolide-induced cell death. We further showed that triptolide down-regulated the expression of c-Myc through targeting ERCC3, a newly identified triptolide-binding protein.ConclusionsThe triptolide-induced modulation of c-Myc/miRNA clusters/target genes axis enhances its potent antitumor activity, which indicates that triptolide serves as an attractive chemotherapeutic agent against HCC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0698-2) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 79%

C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells

Shi

Yuan

et al. 2018

J Exp Clin Cancer Res

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“…Triptolide has the ability to induce senescence. Treatment of liver cancer cells (HepG2) with nanomolar concentrations of triptolide (2.5–10 nM) induced senescence via Akt and hTERT pathway [ 215 ]. Triptolide (3 nM) induced senescence of primary prostate adenocarcinoma cells, as demonstrated by SA- β -gal activity [ 216 ].…”

Section: Nrf2-activating Phytochemicals: Senescence Inducers Senomentioning

confidence: 99%

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Malavolta

Bracci

Santarelli

et al. 2018

Mediators of Inflammation

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The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

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“…Initially, TPL has been demonstrated to cause global transcriptional inhibition via the largest subunit of RNA polymerase II (Zhao et al, 2012). Recently, TPL is believed to target specific transcription factors, such as Bcl-2, Bcl-xL, NF-kB, pRB, RNA polymerases (Wu et al, 2014;Zhang, Ho & Wong, 2018;Li et al, 2017;Guan et al, 2017;Kim & Park, 2017). In this study, we provide evidence that TPL inhibits β-tubulin and HSP90.…”

Section: Discussionmentioning

confidence: 63%

Discovery of potential targets of Triptolide through inverse docking in ovarian cancer cells

Wu¹,

Bao²,

Pan³

et al. 2020

PeerJ

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Triptolide (TPL) is proposed as an effective anticancer agent known for its anti-proliferation of a variety of cancer cells including ovarian cancer cells. Although some studies have been conducted, the mechanism by which TPL acts on ovarian cancer remains to be clearly described. Herein, systematic work based on bioinformatics was carried out to discover the potential targets of TPL in SKOV-3 cells. TPL induces the early apoptosis of SKOV-3 cells in a dose- and time-dependent manner with an IC50 = 40 ± 0.89 nM when cells are incubated for 48 h. Moreover, 20 nM TPL significantly promotes early apoptosis at a rate of 40.73%. Using a self-designed inverse molecular docking protocol, we fish the top 19 probable targets of TPL from the target library, which was built on 2,250 proteins extracted from the Protein Data Bank. The 2D-DIGE assay reveals that the expression of eight genes is affected by TPL. The results of western blotting and qRT-PCR assay suggest that 40 nM of TPL up-regulates the level of Annexin A5 (6.34 ± 0.07 fold) and ATP syn thase (4.08 ± 0.08 fold) and down-regulates the level of β-Tubulin (0.11 ± 0.12 fold) and HSP90 (0.21 ± 0.09 fold). More details of TPL affecting on Annexin A5 signaling pathway will be discovered in the future. Our results define some potential targets of TPL, with the hope that this agent could be used as therapy for the preclinical treatment of ovarian cancer.

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Triptolide inhibits tumor growth by induction of cellular senescence

Cited by 20 publications

References 31 publications

C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells

C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Discovery of potential targets of Triptolide through inverse docking in ovarian cancer cells

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