## 4 Role of Triterpenoids in Cancer Prevention
### Role of Triterpenoids in Inflammation
Ursolic acid inhibited lkB\(\alpha\) degradation, lkB\(\alpha\) phosphorylation, IKK activation, p65 phosphorylation, p65 nuclear translocation, and NF-kB-dependent reporter gene expression. Ursolic acid also inhibited NF-kB-dependent reporter gene expression activated by TNF receptor (TNFR), TNFR-associated death domain (TRADD), TNFR-associated factor (TRAF), NF-kB-inducing kinase (NIK), IKK, and p65 [125]. CDDO and CDDO-Me, two potent oleanane triterpenoids having structures similar to unsolic acid, are currently in Phase I clinical trials for the treatment of leukemia and solid tumors. CDDO blocks the action of NF-kB by preventing the nuclear translocation of p65; this blocks the transactivation of the _NOS2_ and _PTGS2_ genes, thus playing an anti-inflammatory role and causing cell cycle arrest. Cucurbitacin combined with CDDO has been shown to bring about apoptosis by inhibiting NF-kB activation, lkB\(\alpha\) phosphorylation and degradation, NF-kB-reporter gene expression induced by TNF, and STAT signaling. Some other triterpenoids like astragaloside, boswellic acids, calclastrol, ganoderiol F, and gypenoside also blocked the action of NF-kB, inhibiting the transactivation of _cox-2_[44, 51, 171, 172, 173]. CDDO, at nanomolar concentrations, suppresses the _de novo_ synthesis of the inflammatory enzymes iNOS and COX-2 in activated macrophages because they contain \(\alpha\),\(\beta\)-unsaturated carbonyl moieties. Since iNOS and COX-2 overexpression have been implicated as possible enhancers of carcinogenesis, CDDO has potential to be used as a chemoprevertive agent. Furthermore, CDDO may also serve as a chemotherapeutic agent, as micromolar to nanomolar concentrations effectively induced differentiation of human myeloid leukemia cells, inhibited the proliferation of various human tumor cell types, and induced apoptosis in human myeloid and lymphocytic leukemia cells, osteosarcoma cells, and breast cancer cells, including cell lines resistant to chemotherapy [160]. Boswellic acids, a type of pentacyclic triterpeneoid, have been shown to induce apoptosis in different cancer cells. At the molecular level, these compounds inhibit constitutively activated NF-kB signaling by intercepting the IKK activity; signaling through the IFN-stimulated response element remained unaffected, suggesting specificity for IKK inhibition [45, 46]. In a xenograph study of animal meningioma cells, boswellic acids were found to have potent cytotoxic activity with IC\({}_{50}\) values in the range of 2-8 \(\upmu\)M. At low micromolar concentrations, boswellic acids rapidly and potently inhibited the phosphorylation of ERK-1/2 and impaired the motility of meningioma cells stimulated with platelet derived growth factor (PDGF) BB. The cytotoxic action of boswellic acids on meningioma cells may be mediated, at least in part, by the inhibition of the ERK signal transduction pathway, which plays an important role in signal transduction and tumorigenesis [174]. Platycodon, a triterpen isolated from _Platycodon grandiforum_, showed chemopre effects on tumor invasion and migration in HT-1080 tumor cells. Platycodon reduced PMA-enhanced MMP9 and MMP2 activation in a dose dependent manner. Platycodon suppressed PMA enhanced expression of MMP9 protein as well as mRNA and transcription activity levels through the suppression of NF-kB activation without changing the TIMP1 levels. Platycodon also reduced PMA-enhanced expression of MMP2 active forms through the suppression of membrane-type 1 MMP (MT1-MMP), but playcodon did not alter MMP2 and TIMP2 levels. Moreover, ROS production induced by PMA was partly decreased in the presence of platycodon, and this suppression of ROS production may be related to diminished NF-kB activity [175]. In this case, NF-kB inhibition is totally ROS mediated, and most of these ROS are released from glucose molecules that are present on the side chain. Platycodon has been shown to be cytotoxic and to inhibit telomerase activity by downregulating hTERT expression at concentrations between 10 and 20 uM.