Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-κB activation

Abstract

TNF-related apoptosis-inducing ligand (TRAIL/Apo- 2L), a newly identified member of the TNF family promotes apoptosis by binding to the transmembrane receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL known to activate NF-kappaB in number of tumor cells including A549 (wt p53) and NCI-H1299 (null p53) lung cancer cells exerts relatively selective cytotoxic affects to the human tumor cell lines without much effect on the normal cells. We set out to identify an agent that would sensitize lung cancer cells to TRAIL-induced apoptosis through inhibition of NF-kappaB activation. We found that triptolide, an oxygenated diterpene extracted and purified from the Chinese herb Tripterygium wilfordii sensitized A549 and NCI-H1299 cells to TRAIL-induced apoptosis through inhibition of NF-kappaB activation. Pretreatment with MG132 which is a well-known NF-kappaB inhibitor by blocking degradation of IkappaBalpha also greatly sensitized lung cancer cells to TRAIL-induced apoptosis. Triptolide did not block DNA binding of NF-kappaB activated by TRAIL as in the case of TNF-alpha. It has been already proven that triptolide blocks transactivation of p65 which plays a key role in NF-kappaB activation. These observations suggest that triptolide may be a potentially useful drug to enhance TRAIL-induced tumor killing in lung cancer.

Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor ?B

“…9A) or in the medium (data not shown) were not detected over 20 minutes, and subsequently began to increase. The proteasome inhibitor MG132, which is a well-known NF-B inhibitor by blocking degradation of I B␣, [26][27][28] was employed for further confirmation of hypothesis that TNF-␣ production induced by Con A was NF-B-mediated. MG132 reduced either intracellular TNF-␣ production 30 and 60 minutes after Con A stimulation (Fig.…”

“…One important signaling pathway in the induction of TNF expression leads to activation of the transcription factor NF-B. 26,34,35 Inhibiting gene expression through the direct modulation of transcription factors may provide exciting potential therapeutic targets, especially if a tissue-specific regulation of TNF-␣ production is unraveled. Recently, Manna and Aggarwal demonstrated that treatment of a human T-cell line (Jurkat) with leflunomide blocks NF-B activation mediated by many inflammatory agents, including phorbol ester, TNF-␣, lipopolysaccharide, H 2 O 2 , okadaic acid, and ceramide.…”

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

“…Thus, inhibitors of NF-κB are of interest as potential antiinflammatory drugs. Natural products of several types, including lignans (Hwang et al, 2003), sesquiterpene esters (Jin et al, 2002) and sesquiterpene lactones Schorr et al, 2002), have been found to interfere with various steps in NF-κB release and activation of DNA transcription (Lee et al, 2002a). Genes involved in inflammation can also be activated by other transcription factors, such as activator protein-1 (AP-1), nuclear factor of activated T cells (NFAT), and Oct-1, and by the p38 mitogen-activated protein (MAP) kinase pathway (Barnes and Karin, 1997;Diehl et al, 2004;Pinna et al, 2004;Wang et al, 2004a).…”

“…Whether any components of the Tripterygium extract interfere with AP-1 activity remains controversial (Maekawa et al, 1999;Sylvester et al, 2001;Wang et al, 2004a). Pure triptolide (1) did not affect DNA binding of NF-κB; rather, it inhibited the transcription of proinflammatory genes by blocking the transactivation of NF-κB, which occurs after its binding to promoter regions of these genes Lee et al, 2002a). Triptolide (1) also inhibited transactivation by NFAT and upregulation of the nucleotide-binding activity of Oct-1 Wang et al, 2004a).…”

“…Triptolide (1) has shown antiproliferative and apoptotic effects in several tumor lines in vitro (Kutney et al, 1997;Tengchaisri et al, 1998;Kiviharju et al, 2002;Yang et al, 2002;Choi et al, 2003) and restricted tumor growth, or shrank tumors, in animals (Tengchaisri et al, 1998;Yang et al, 2002). By suppressing activation of NF-κB, 1 made tumor cells more sensitive to TNF-α-induced apoptosis (Lee et al, , 2002a. Triptolide (1) also showed synergistic effects with other chemotherapeutic agents Fidler et al, 2003).…”