Parthenolide sensitizes hepatocellular carcinoma cells to trail by inducing the expression of death receptors through inhibition of STAT3 activation

Carlisi, Daniela; D’Anneo, Antonella; Angileri, Liliana; Lauricella, Marianna; Emanuele, Sonia; Santulli, Andrea; Vento, Renza; Tesoriere, Giovanni

doi:10.1002/jcp.22494

Cited by 83 publications

(73 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous it was reported that a decrease in the phosphorylated form of STAT3 could be responsible for the enhanced expression of death receptor (25). In this study, we found that bufotalin together with TRAIL inhibited STAT1 and STAT3 phosphorylation, and induced DR5 mRNA and protein expression, indicating that bufotalin may enhance TRAIL-induced death receptor expression through STAT3.…”

Section: Discussionsupporting

confidence: 53%

Bufotalin sensitizes death receptor-induced apoptosis via Bid- and STAT1-dependent pathways

Sakurai

2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. Tumor necrosis factor-alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are apoptosis-inducing ligands that stimulate death receptors. In this study, we investigated the effects of bufotalin, a major compound in toad venom, on sensitizing TNF-α and TRAIL-induced apoptosis of HeLa cells. Bufotalin promoted death receptor-mediated cell death, especially TRAIL-induced apoptosis, through activation of caspase-3 and PARP-1. Mitochondrial Bid-dependent pathway was activated in TNF-α-induced cell death. Cotreatment of bufotalin with TRAIL resulted in the downregulation of antiapoptotic proteins, including Bcl-XL, Mcl-1, survivin and XIAP, and the up-regulation of MAPKs and TRAIL receptor DR5. In addition, phosphorylation of STAT1 was strongly inhibited by bufotalin. Moreover, DR5 expression was induced by knocking down the STAT1 expression. Moreover, the TRAIL-induced apoptotic response was promoted by STAT1 siRNA. Our results demonstrated that bufotalin is a powerful sensitizer of death receptor-induced apoptosis in cancer cells. IntroductionMany chemotherapeutic agents induce tumor cell death by apoptosis. Apoptosis can be initiated by two distinct pathways: through mitochondria (intrinsic pathway) or through death receptors on the cell surface (extrinsic pathway). Induction of apoptosis via the intrinsic pathway leads to the breakdown of mitochondrial membrane potential and release of cytochrome c, and subsequently results in the activation of procaspase 9 within the so-called apoptosome (1). In addition, death ligands binding to the death receptors, including Fas, tumor necrosis factor receptor 1 (TNF-R1) or TNF-related apoptosis-inducing ligand (TRAIL) receptor DR4/5, trigger extrinsic apoptosis pathways.TNF-α binds to TNF-R1, which recruits the adaptor molecule TRADD and FADD to activate a caspase cascade from the upstream initiator caspase-8 to the downstream effector caspase-3 (2,3). TRAIL is known to induce apoptosis in a variety of tumor cells through its action with two distinct receptors, DR4 and DR5. Bid, a member of the Bcl-2 family, is the main molecular linker connecting the death receptor pathway and the mitochondrial pathway. Bid can activate mitochondria via direct interaction with Bax or Bak. Cytosolic Bid is cleaved by caspase-8 at the amino terminus to generate a truncated form of Bid (tBid) that mediates cytochrome c release from mitochondria, which serves as an amplification signal by activating downstream effector caspases, including caspase-3 (4-8). Procaspase-3 can also be directly cleaved by caspase-8 in a mitochondrion-independent manner. In turn, effector caspases are responsible for cleaving cellular proteins, such as poly(ADP-ribose) polymerase (PARP) (9). Caspase cascade can be blocked by anti-apoptosis proteins, such as cIAP1/2, Bcl-xl, Mcl-1, Survivin and XIAP (10).Chan Su, toad venom, is a traditional Chinese medicine from the skin secretions of Bufo bufogargarizans Cantor and B. melsanostictus Schneider. It has been used to treat various diseases such as card...

show abstract

Section: Discussionsupporting

confidence: 53%

Bufotalin sensitizes death receptor-induced apoptosis via Bid- and STAT1-dependent pathways

Sakurai

2011

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…Recent publications suggest that parthenolide-mediated effects on death receptors depend on a reduction in levels of phosphorylated and active forms of STAT proteins [41], which may be due to an inhibitory effect of PN on activation of JAK proteins. Among important members of the TNF family, the TNF-related apoptosis-inducing ligand (TRAIL), also known as the Apo-2 ligand, is found to interact with five distinct TRAIL receptors [42,43].…”

Section: Parthenolide-mediated Stat Inhibitionmentioning

confidence: 99%

Parthenolide, a Sesquiterpene Lactone, Expresses Multiple Anti-cancer and Anti-inflammatory Activities

et al. 2011

View full text Add to dashboard Cite

Parthenolide, a naturally occurring sesquiterpene lactone derived from feverfew (Tanacetum parthenium), exhibits exceptional anti-cancer and anti-inflammatory properties, making it a prominent candidate for further studies and drug development. In this review, we briefly investigate molecular events and cell-specific activities of this chemical in relation to cytochrome c, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), signal transduction and activation of transcription (STAT), reactive oxygen species (ROS), TCP, HDACs, microtubules, and inflammasomes. This paper reports that parthenolide shows strong NF-κB- and STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes. This compound acts both at the transcriptional level and by direct inhibition of associated kinases (IKK-β). Similarly, this review discusses parthenolide-induced ROS-mediated apoptosis of tumor cells via the intrinsic apoptotic signaling pathway. The unique ability of this compound to not harm normal cells but at the same time induce sensitization to extrinsic as well as intrinsic apoptosis signaling in cancer cells provides an important, novel therapeutic strategy for treatment of cancer and inflammation-related disorders.

show abstract

“…Twenty-four hours after seeding, cells were treated with drugs for the time indicated in the Results. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay as previously reported (16). MTT is reduced to purple formazan in the mitochondria of living cells.…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

The oxygen radicals involved in the toxicity induced by parthenolide in MDA-MB-231 cells

et al. 2014

Self Cite

View full text Add to dashboard Cite

Abstract.It has been shown that the sesquiterpene lactone parthenolide lowers the viability of MDA-MB-231 breast cancer cells, in correlation with oxidative stress. The present report examined the different radical species produced during parthenolide treatment and their possible role in the toxicity caused by the drug. Time course experiments showed that in the first phase of treatment (0-8 h), and in particular in the first 3 h, parthenolide induced dichlorofluorescein (DCF) signal in a large percentage of cells, while dihydroethidium (DHE) signal was not stimulated. Since the effect on DCF signal was suppressed by apocynin and diphenyleneiodonium (DPI), two inhibitors of NADPH oxidase (NOX), we suggest that parthenolide rapidly stimulated NOX activity with production of superoxide anion (O 2•-

show abstract

Parthenolide sensitizes hepatocellular carcinoma cells to trail by inducing the expression of death receptors through inhibition of STAT3 activation

Cited by 83 publications

References 52 publications

Bufotalin sensitizes death receptor-induced apoptosis via Bid- and STAT1-dependent pathways

Bufotalin sensitizes death receptor-induced apoptosis via Bid- and STAT1-dependent pathways

Parthenolide, a Sesquiterpene Lactone, Expresses Multiple Anti-cancer and Anti-inflammatory Activities

The oxygen radicals involved in the toxicity induced by parthenolide in MDA-MB-231 cells

Contact Info

Product

Resources

About