Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F

Abstract

Background Despite significant progress in diagnostics and therapeutics, over fifty thousand patients die from colorectal cancer annually. Hence there is urgent need for new lines of treatment. Triptolide, a natural compound isolated from the Chinese herb Tripterygium wilfordii, is effective against multiple cancers. We have synthesized a water soluble analog of triptolide, named Minnelide, which is currently in phase I trial against pancreatic cancer. The aims of the current study were to evaluate whether triptolide/Minnelide is effective against colorectal cancer and to elucidate the mechanism by which triptolide induces cell death in colorectal cancer. Methods Efficacy of Minnelide was evaluated in subcutaneous xenograft and liver metastasis model of colorectal cancer. For mechanistic studies colon cancer cell lines HCT116 and HT29 were treated with triptolide and the effect on viability, caspase activation, annexin positivity, lactate dehydrogenase(LDH) release and cell cycle progression was evaluated. Effect of triptolide on E2F transcriptional activity, mRNA levels of E2F dependent genes, E2F1-Rb binding and proteins levels of regulator of G1-S transition was also measured. DNA binding of E2F1 was evaluated by chromatin immunoprecipitation assay. Results Triptolide decreased colon cancer cell viability in a dose- and time-dependent fashion. Minnelide markedly inhibited the growth of colon cancer in the xenograft and liver metastasis model of colon cancer and more than doubles the median survival of animals with liver metastases from colon cancer. Mechanistically we demonstrate that at low concentrations, triptolide induces apoptotic cell death but at higher concentrations it induces cell cycle arrest. Our data suggest that triptolide is able to induce G1 cell cycle arrest by inhibiting transcriptional activation of E2F1. Our data also show that triptolide downregulates E2F activity by potentially modulating events downstream of DNA binding. Conclusion Triptolide and Minnelide are effective against colon cancer in multiple pre-clinical models.

Retracted: Triptolide inhibits the proliferation and migration of medulloblastoma Daoy cells by upregulation of microRNA‐138

“…33 Thus, inducing cancer cell apoptosis and inhibiting cancer cell proliferation are arguably the potent therapeutic methods for cancer treatment. [14][15][16][17][18] In this study, TPL significantly inhibited the proliferation of medulloblastoma Daoy cells and remarkably promoted Daoy cell apoptosis. [14][15][16][17][18] In this study, TPL significantly inhibited the proliferation of medulloblastoma Daoy cells and remarkably promoted Daoy cell apoptosis.…”

“…11,12 Triptolide (TPL) is the major active component extracted from the Chinese medicine herb Tripterygium wilfordii Hook F. 13 Reno et al 14 demonstrated that TPL inhibited the migration, invasion, and metastasis of lung cancer cells. Oliveira et al 16 proved that TPL abrogated the growth of colon cancer and induced cell cycle arrest by suppressing transcriptional activation of E2F. Oliveira et al 16 proved that TPL abrogated the growth of colon cancer and induced cell cycle arrest by suppressing transcriptional activation of E2F.…”

ITRAQ-Based Proteomics Analysis of Triptolide On Human A549 Lung Adenocarcinoma Cells

“…Many studies have shown that TP inhibits cell growth and induces apoptosis in various cancers, primarily through multiple mechanisms, including the suppression of various signaling pathways and proliferative and antiapoptotic factors in a given cell type and under specific conditions. TP has been reported to strongly inhibit the transcription of numerous proinflammatory mediators [25]and was also implicated as a potent inhibitor of NF-kappa B and a promoter of transcriptional arrest [26][27][28][29][30]. Recent studies have shown that TP inhibits RNA polymerase-mediated transcription by targeting transcription factors, leading to the down-regulation of certain mRNA molecules [31][32][33].…”

Triptolide induces cell apoptosis in human stomach cancer cell via caspase 3-dependent cascade pathway

“…In addition, triptolide is also able to cause pancreatic cancer cell death through induction of apoptosis via inhibition of HSP70 [12]. Triptolide has also been demonstrated to abrogate cell growth of colon cancer and induce cell cycle arrest through inhibiting transcriptional activation of E2F [14]. A recent study also suggests that the induction of cell death by triptolide is modified by autophagy in cardiomyocytes [15].…”