## 4 Role of Triterpenoids in Cancer Prevention
### Role of Triterpenoids in Tumor Cell Survival, Apoptosis, and Proliferation
Avicins downregulate both STAT3 and the expression of STAT3-regulated prosurvival proteins, which contribute to the induction of apoptosis in tumor cells. STAT3 plays an important role in inflammation and wounding, and the _in vivo_ inhibition of VEGF. In a mouse skin carcinogenesis model, avicins inhibited the expression of STAT3, resulting in the suppression of the pro-inflammatory and pro-oxidant stromal environment of tumors [11]. Avicins at concentrations of 0.5-5.0 \(\mathrm{\SIUnitSymbolMicro m}\) caused more apoptosis in patients' Sezary cells than in healthy donors' CD4+ T cells and activated CD4+ T cells and decreased apoptosis inhibitors bcl-2 and survivin [13]. Furthermore, avicin D-induced autophagic cell death was abrogated by knockdown of tuberous sclerosis complex 2 (TSC2), a key mediator linking AMP-activated protein kinase (AMPK) to mTOR inhibition, suggesting that AMPK activation is a crucial event targeted by avicins. Avicins also have been shown to lower energy of metabolism in tumor cells by targeting the outer mitochondrial membrane, causing cancer cell death [187]. Tumor cells generate hydroperoxides at a very high rate, and avicins could provide a new strategy of anticancer therapy by sensitizing cells with high levels of ROS to apoptosis. In another study, boswellic acids, which inhibit STAT3 activation, led to the suppression of gene products involved in proliferation (cyclin D1), survival (Bel-2, Bcl-xL, and Mcl-1), and angiogenesis (VEGF) [32]. Maslinic acid has shown an antiproliferative effect against Caco-2 cancer cells (EC\({}_{50}\) = 15 \(\upmu\)M), HT-29 human colon cancer cells (EC\({}_{50}\) = 74 \(\upmu\)M), 1321N1 astrocytoma cells (EC\({}_{50}\) = 25 \(\upmu\)M), and human leukemia cells (CCRF-CEM and CEM/ADR5000) (EC\({}_{50}\) = 7 and 9 \(\upmu\)M, respectively). Maslinic acid's antiproliferative activity likely comes from the induction of an oxidative apoptotic pathway, which causes cell cycle and cytoskeleton alterations. Maslinic acid has been found to attenuate intracellular oxidative stress by inhibiting of NO and H\({}_{2}\)O\({}_{2}\) production and reducing proinflammatory cytokine generation in murine macrophages [205]. Maslinic acid inhibited cell growth with an EC\({}_{50}\) of 101.2 \(\upmu\)M without necrotic effects. This effect of maslinic acid is caused by a hydroxyl group at the carbon 2 position, ultimately activates caspase-3 as a prime apoptosis protease [206]. A 200 \(\upmu\)M concentration of maslinic acid was sufficient for activating caspase-3, which inhibits cell proliferation [207]. Maslinic acid from pomace olive oil demonstrated a suppressive effect on oxidative stress and cytokine production in stimulated murine macrophages [208]. Triterpenoid isolated from apple peels have shown potent antiproliferative activity and may be partially responsible for apples' anticancer activity. Saikosaponins prevented the proliferation of MCF-7 cell at the concentration of 10 nM to 10 \(\upmu\)M and was significantly inhibited by the specific estrogen receptor (ER) antagonist ICI-182780 [209]. This antiproliferative effect is due to the synthesis of extracellular matrix proteins through the downregulation of the _CDK4_, _c-Jun_, and _c-Fos_ genes [210], which block cell cycle progression at the G1 phase. The potency of unsolic acid was associated with ZIP/p62 and protein kinase C-zeta (PKC-zeta). Ursolic acid inhibited the interaction of ZIP/p62 and PKC-zeta. It also further suppressed the activation of NF-kB and the downregulation of the MMP9 protein, which in turn contributed to unsolic acid's inhibitory effects on IL-1B or TNF-induced C6 glioma cell invasion [127]. Ursolic acid showed the strongest inhibitory activity to urokinase (IC\({}_{50}\) = 12 \(\upmu\)M) and cathepsin B (IC\({}_{50}\) = 10 \(\upmu\)M), and as proteases are involved in tumor invasion and metastasis, this activity could be beneficial in cancer treatment [211].