## 4 Role of Triterpenoids in Cancer Prevention
### Role of Triterpenoids in Inflammation
Treatment of cells with dithiothreitol (DTT) totally reversed the avicin G-induced inhibition of NF-\(\kappa\)B activity, suggesting that sulfhydryl groups critical for NF-\(\kappa\)B activation were being affected. Avicin G treatment decreased the expression of NF-\(\kappa\)B regulated proteins such as iNOS and COX-2 [16]. Other studies showed that pretreating cells with triterpenoids for 24 hours significantly reduced the induction of NF-\(\kappa\)B mediated through TNF-\(\alpha\)[44, 167]. Pristimerin, a natural triterpenoid, elicits cellular responses closely resembling those elicited by proteasome inhibitors, such as the rapid induction of heat shock proteins (HSPs), activating transcription factor 3 (ATF3), and C/EBP homologous protein (CHOP). Pristimerin also inhibits NF-\(\kappa\)B activation by inhibiting IKK-\(\alpha\) or IKK-\(\beta\), whereas proteasome inhibitors instead suppress NF-\(\kappa\)B function by impairing the degradation of ubiquitinated \(\mathrm{I}\kappa\)B. By inhibiting both IKK and the proteasome, pristimerin suppresses the activation of constitutive NF-\(\kappa\)B in myeloma cells. Multiple myeloma is exquisitely sensitive to proteasome or NF-\(\kappa\)B pathway inhibition. Consistent with this, pristimerin has been shown to be potently and selectively lethal to primary myeloma cells (IC\({}_{50}\) \(<\) 100 nM) and to inhibit xenografted plasmocytoma tumors in mice [118]. Pristimerin is also known as an antifungal, antimicrobial, and anti-inflammatory plant compound with an effect on the iNOS system in LPS-activated RAW 264.7 macrophages [168]. Celastrol, a natural triterpenoid with a structure similar to that of pristimerin, is found in the thunder god vine and was identified as having potential for use in cancer treatment because of its ability to enhance the death of melanoma cells. Celastrol also inhibited cell proliferation in melanoma cells. When celastrol was used to treat melanoma cells, it (like pristimerin) increased levels of ubiquitinated proteins, reduced levels of TNF-\(\alpha\)-induced \(\mathrm{I}\kappa\)B phosphorylation, and blocked NF-\(\kappa\)B translocation to the nucleus at nanomolar concentrations; however, the molecular mechanism for these effects differed. Celastrol normally inhibits LPS-induced phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinases 1/2 (MAPK/ERK1/2) and the DNA binding activity of NF-\(\kappa\)B [49]. Other studies have indicated that TNF-induced IKK activation requires the activation of TAK1 and that celastrol inhibits the TAK1-induced NF-\(\kappa\)B activation [52]. Celastrol also suppressed the ovalbumin-induced airway inflammation, hyperresponsiveness, and tissue remodeling by regulating the imbalance of matrix metalloproteinase 2 and 9 (MMP2, MMP9) and tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2) by inflammatory cytokines through MAP kinases and NF-kB in inflammatory cells. The triterpen erythroidol and macdassic acid are structural analogues of each other and have antiproliferative and anticancer activity. However, only macdassic acid has also shown LPS-stimulated NF-kB inhibition with subsequent blocking of p65 protein translocation to the nucleus [103]. This may be because of the presence of an additional hydroxyl at carbon 2, which play an important role in the electrophilic reaction. Maslinic acid, which is similar to macdassic acid, also inhibits NF-kB translocation. Maslinic acid also inhibited p50, p65, and NF-kB translocation in a dose-dependent manner in both unstimulated and phorbol-myristate acetate (PMA)-challenged cells, being particularly effective on the p50 subunit [169]. Momordin, an analogue of maslinic acid, does not contain any hydroxyl group at the carbon 2 position but still it has shown NF-kB inhibition in osteoclast differentiation. This may be because of momordin's action on c-Fos, a component of the activating protein-1 (AP-1) transcription factor that plays a key role in osteoclast differentiation.