Synthetic Triterpenoids Cooperate with Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand to Induce Apoptosis of Breast Cancer Cells

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) has been shown to induce apoptosis specifically in cancer cells while sparing normal tissues. Unfortunately not all cancer cells respond to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. We have identified synthetic triterpenoids, including 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), which sensitize TRAIL-resistant cancer cells to TRAIL-mediated apoptosis. Here we show that TRAIL-treated T47D and MDA-MB-468 breast cancer cells fail to initiate detectable caspase-8 processing and, consequently, do not initiate TRAIL-mediated apoptosis. Concomitant treatment with CDDO or CDDO-Im reverses the TRAIL-resistant phenotype, promoting robust caspase-8 processing and induction of TRAIL-mediated apoptosis in vitro. The combination of triterpenoids and monoclonal anti-TRAIL receptor-1 (DR4) antibody also induces apoptosis of breast cancer cells in vitro. From a mechanistic standpoint, we show that CDDO and CDDO-Im down-regulate the antiapoptotic protein c-FLIP L , and up-regulate cell surface TRAIL receptors DR4 and DR5. CDDO and CDDO-Im, when used in combination with TRAIL, have no adverse affect on cultured normal human mammary epithelial cells. Moreover, CDDO-Im and TRAIL are well tolerated in mice and the combination of CDDO-Im and TRAIL reduces tumor burden in vivo in an MDA-MB-468 tumor xenograft model. These data suggest that CDDO and CDDO-Im may be useful for selectively reversing the TRAILresistant phenotype in cancer but not normal cells. (Cancer Res 2005; 65(11): 4799-808)

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

“…Recently, several chemopreventive agents such as triterpenoids, silibinin, and flavopiridol have been shown to induce down-regulation of c-FLIP and subsequent sensitization to TRAIL-induced apoptosis in cancer cells [36][37][38]. In this study, we found that treatment of Caki cells with Wit A induced significant down-regulation of both c-FLIP L and c-FLIP S , suggesting that Wit A-induced loss of c-FLIP expression may underlie the observed sensitization to TRAIL.…”

Nuclear Factor κB Inhibitors Alleviate and the Proteasome Inhibitor PS-341 Exacerbates Radiation Toxicity in Zebrafish Embryos

“…Direct NF-κB inhibitors also exert antineoplastic effects in select model systems as shown extensively for CDDO-TFEA and derivatives thereof. [51][52][53][54][55][56][57] These findings are consistent with a favorable therapeutic window for NF-κB inhibitors when used in combination with radiation and, potentially, chemotherapeutic drugs. …”

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

“…FLIP has been found to be overexpressed in many human cancers (Ryu et al, 2001;Zhou et al, 2004;Valnet-Rabier et al, 2005), and has emerged through our work and that of others, as a potential anti-cancer drug target (Hyer et al, 2005;Wilson et al, 2007). Furthermore, XIAP has been found to be overexpressed in several cancers, and small molecule and antisense approaches to target XIAP are in development (Hu et al, 2003;LaCasse et al, 2006).…”