## 4 Role of Triterpenoids in Cancer Prevention
### Role of Triterpenoids in Tumor Cell Survival, Apoptosis, and Proliferation
In addition to this, pristimerin showed that c-Jun N-terminal kinase (JNK) was involved in ROS-dependent Bax activation, which increases intracellular ROS, JNK activation, conformational change, and mitochondrial redistribution of Bax, mitochondrial membrane potential loss, and cell death. Pretreatment with pristimerin also activated PARP-1 [117]. Another study showed that pristimerin induced apoptosis by targeting the proteasome in prostate cancer cells. This may be because of the accumulation of ubiquitinated proteins and three proteasome target proteins, Bax, p27 and lkB\({}_{\alpha}\), in androgen receptor (AR)-negative PC-3 prostate cancer cells, which supports the conclusion that proteasome is inhibited by pristimerin [120]. Another study showed that this apoptosis might be induced by pristimerin through the direct effect of caspase on mitochondria in MDA-MB-231 cells [119]. Pristimerin showed antiviral activity by inhibiting the viral DNA synthesis but had no virucidal effect [185]. Celastrol combined with TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) exerted strong synergistic antiproliferative effect against human cancer cells, including those from ovary cancer (OVCAR-8), colon cancer (SW620), and lung cancer (95-D). _In vivo_, the antitumor efficacy of TRAIL/APO-2L was dramatically increased by celastrol. These enhanced anticancer activities were accompanied by the prompt onset of caspase-mediated apoptosis. Celastrol also suppressed the TNF-induced expression of various gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2,Bel-xL, c-FLIP, and survivin), proliferation (cyclin D1 and COX-2), invasion (MMP9), and angiogenesis (VEGF) [52]. Diosgenin-induced apoptosis was associated with COX-2 upregulation in HEL cells [75]. Diosgenin also downregulated gene products involved in cell proliferation (cyclin D1, COX-2, and c-myc) and anti apoptosis (IAP1, Bcl-2, Bcl-xL, Bfl-1/A1, TRAF1, and cFLIP) [64]. Avicins are novel plant derived metabolites that lower energy metabolism in tumor cells by targeting the outer mitochondrial membrane Avicins dephosphorylated STAT3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of STAT3. The expression of STAT3-regulated proteins such as c-myc, cyclin D1, Bcl-2, survivin, and VEGF were reduced in response to avicin treatment. Avicin also induced dephosphorylation of STAT3, dephosphorylation of JAKs, and activation of protein phosphatase-1 [11]. Another study showed that avicins induced apoptosis and downregulated p-STAT3, Bcl-2, and survivin in cutaneous T-cell lymphoma cells. Avicin D did not change STAT3 expression, but it decreased phospho-STAT3 protein levels [13,187]. Betulinic acid inhibited the constitutive activation of STAT3, Src kinase, JAK1, and JAK2. Pervanadate reversed the betulinic acid induced down regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Betulinic acid also downregulated the expression of STAT3 regulated gene products, such as Bcl-xL, Bcl-2, cyclin D1, and survivin. This correlated with an increase in apoptosis as indicated by an increase in the sub-G1 cell population and an increase in caspase-3-induced PARP cleavage [188]. Recently, some researchers found that natural triterpene diols promote apoptosis in astrocytoma cells through ROS-mediated mitochondrial depolarization and JNK activation. Alcohols extracted from olive oil, erythroidiol (an intermediate from oleanolic acid), and its isomer, uvaol, have been reported anticancerous, particularly on brain cancer cells. Erythrodiol and uvaol effectively affected cell proliferation as well as cell cycle phases and induced 1321N1 cell death and modulated the apoptotic response, promoting nuclear condensation and fragmentation. These results may be due to production of ROS with loss of mitochondrial transmembrane potential, and correlated with the activation of JNK.