## 4 Role of Triterpenoids in Cancer Prevention
### Role of Triterpenoids in Tumor Cell Survival, Apoptosis, and Proliferation
Moreover, CDDO combined with TRAIL promoted the induction of apoptosis. CDDO normally acts through both the extrinsic and intrinsic pathways by activating the cleavage of BID and of caspases-3, -8, and -9; by downregulating FLIP; or by inducing the translocation of Bax to the mitochondria and the release of cytochrome C [195, 196, 197]. The antitumor activity of CDDO-Me was associated with the inhibition of p-Akt, mammalian target of rapamycin (mTOR), and NF-\(\kappa\)B signaling proteins and their downstream targets such as p-Bad and p-Foxo3a for Akt; p-S6K1, p-eIF-4E and p-4E-BP1 for mTOR; and COX-2, VEGF and cyclin D1 for NF-\(\kappa\)B [167]. Acetyl-11-keto-\(\beta\)-boswellic acid (AKBA), a derivative of boswellic acid has been shown to induce apoptosis in cancer cells. AKBA mediated inhibition of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway; this pathway is crucial for cell proliferation and survival [198]. Another study showed that cyclin D1 and E, CDK2 and 4 and phosphorylated retinoblastoma protein (Rb) were decreased in AKBA-treated cells, while p21 expression was increased. The growth inhibitory effect of AKBA was dependent on p21 but not p53 [199]. The cytostatic and apoptosis inducing activities of boswellic acids toward malignant cell lines has been shown _in vitro_[200]. Boswellic acids triggered apoptosis by means of a pathway dependent on caspase-8 activation but independent of Fas/Fas ligand interaction in colon cancer cells [201]. AKBA inhibited the NF-kB-dependent reporter gene expression activated by TNFR, TRADD, TRAF2, NIK, and IKK, but not that activated by the p65 subunit of NF-kB, which indicates that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents [46]. In HT-29 human colon cancer cells, platycodon induced apoptosis through DNA fragmentation and PARP cleavage. The apoptosis induced by platycodon was associated with the activation of initiator caspases-8 and -9 as well as effector caspase-3. Platycodon stimulated Bid cleavage, indicating that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. It increased the expression of the proapoptotic protein Bax and decreased the expression of the antiapoptotic protein Bcl-2. Platycodon also increased the expression of the caspase-independent mitochondrial apoptosis factor, apoptosis inducing factor (AIF), in HT-29 cells. Thus, platycodon exerts its apoptotic effect via both caspase-dependent and caspase-independent pathways [116,202,203]. A few tr triterpenoid compounds have been shown to both activate caspase activity and downregulate the expression of Bcl-2 or Bcl-xL. The ability to suppress proliferation and induce apoptosis in human cancer cells is clearly important for drugs targeting either malignant cells in treatment or premalignant cells in prevention. One of the hallmarks of cancer is aggressive proliferation of cells. In a normal cell, a fine balance between growth signals and antigrowth signals regulates proliferation. However, this fine orchestration is lost in cancer cells, which often show uncontrolled growth due to the loss of both growth-controlling factors. On one hand, cancer cells acquire the capability to generate their own growth signals, while on the other hand, they also become unresponsive to antigrowth signals [204]. Numerous factors regulate the natural progression of a normal cell. Some of these factors, such as cyclins, are upregulated in cancer cells, causing the cells to replicate uncontrollably. Cyclins are the regulatory proteins that control the cell cycle, while other factors such as COX-2 and c-myc play a supporting role. The most commonly affected cyclin in cancer cells is cyclin D1, an important cell cycle regulator that plays a role in transition of the cell from the G1 phase to the S phase. Cancer cells show overexpression of this cyclin D1 and thus it has been linked to the development and progression of cancer.