## 4 Role of Triterpenoids in Cancer Prevention
### Role of Triterpenoids in Tumor Cell Survival, Apoptosis, and Proliferation
The presence of catalase reversed the triterpene diols induced mitochondrial depolarization, JNK activation, and apoptotic death, indicating the critical role of ROS in the action of diols ring compounds [189]. Oleanolic acid also upregulated COX-2 expression and induced prostacyclin (PGI2) synthesis. These effects may be as a result of the early activation of cAMP regulatory element-binding protein (CREB), a key transcription factor involved in COX-2 transcriptional upregulation. Oleanolic acid has also shown cardioprotective effects [190]. Maslinic acid is present in high concentrations in olive pomace. Various studies have examined the responses of HT-29 and Caco-2 colon cancer cell lines to maslinic acid treatment. It also induced strong G0/G1 cell-cycle arrest and DNA fragmentation, and increased caspase-3 activity. However, maslinic acid did not alter the cell cycle or induce apoptosis in the non-tumorous intestinal cell lines IEC-6 and IEC-18 [191]. Momordin inhibited proliferation and induced apoptosis in human promyelocytic leukemia (HL-60) cells and was cytotoxic to HL-60 cells with an IC\({}_{50}\) of 19.0 \(\upmu\)g/mL. The antiproliferative effects of momordin appear to be attributable to its induction of apoptotic cell death, as momordin induced nuclear morphology changes and internucleosomal DNA fragmentation and increased the proportion of hypodiploid cells. Momordin decreased the expression of the antiapoptotic protein Bcl-2 but increased the expression of the proapoptotic protein Bax. In addition, treatment with momordin induced the activation of caspase-3 and the cleavage of PARP [105]. Many of the triterpenoids derived from nature, target caspases, which are essential for apoptotic cell death. Saikosaponins were found to be cytotoxic in different cancer cell lines and to exert significant inhibition of nitric oxide production in LPS-induced RAW 264.7 macrophages, with IC\({}_{50}\) of 4.2 and 10.4 uM, respectively [170]. Saikosaponins have shown a variety of pharmacological and immunomodulatory activities, including anti-inflammatory, antibacterial, antiviral and anticancer effects. Treatment of MDA-MB-231 with saikosaponin-A increased the population of cells in the sub-G1 phases of the cell cycle. These results showed that apoptosis in MDA-MB-231 cells was independent of the p53/p21 pathway mechanism and was accompanied by an increased ratio of Bax to Bcl-2, increased c-myc levels, and increased activation of caspase-3. In contrast, apoptosis of MCF7 cells may have been initiated by the Bcl-2 family of proteins and involved the p53/p21-dependent pathway mechanism, and it was accompanied by an increased level of c-myc protein [192]. In another study, an enhancement in Fas and its two ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), as well as Bax protein, was shown to be responsible for the apoptotic effect induced by saikosaponins [121]. Saikosaponins significantly increased the levels of c-myc and p53 mRNA [193]. Saikosaponins also caused G0/G1 cell cycle arrest of activated T cells by downregulating the protein levels of CDK6 and cyclin D3 and upregulating the protein level of p27(kip) [194]. The inhibition of NF-\(\kappa\)B activation by unsolic acid correlated with the suppression of NF-\(\kappa\)B dependent cyclin D1, COX-2, and MMP9 expression [125]. Ursolic acid blocked cell cycle progression in the G1 phase and was associated with a marked decrease in the protein expression of cyclin D1, D2, and E, and their activating partners cdk2, cdk4, and cdk6 with concomitant induction of p21. The accumulation of p21/WAF1 might be p53 dependent. The accumulation of p21/WAF1 correlated with the upregulation of Fas, the Fas ligands and Bax, and the downregulation of NF-\(\kappa\)B, Bcl-2, and Bcl-\(\kappa\)L [121]. Ursolic acid also upregulated apoptotic genes _p53_ and _caspase-3_, while the antiapoptotic gene _Bcl-2_ was downregulated [124]. CDDO, concentrated at 1-5 uM, induced apoptosis in various cancer cell lines.