# The Potential Role of Timosaponin-AIII in Cancer Prevention and Treatment
## 4 The Anticancer Effects of TSAIII
### Anti-Inflammation  
Inflammation has been implicated in various diseases, such as cancer, obesity, diabetes, AD, and osteoarthritis. The activation of the arachidonic acid (AA) cascade results in the overexpression of COX-2 and 5-lipoxygenase (5-LOX). COX-2 and 5-LOX are two independent pathways that contribute to inflammatory responses. The inhibition of one of these pathways could switch the metabolism of AA to the other. The dual inhibition of the COX-2 and 5-LOX pathways might be effective for inflammatory diseases. TSAIII has been identified as the dual inhibitor of COX-2 and 5-LOX enzymes, with IC50 values of 1.81 uM and 1.21 uM, respectively [91]. Chronic inflammatory reactions participate in the pathogenesis of benign prostatic hyperplasia (BPH). Specifically, AA metabolism-associated COX-2 stimulates the occurrence and development of BPH by inducing local vasodilation and increasing vascular permeability. TSAIII is one of the bioactive components in the Zi-shen pill, which improves pathological changes in BPH by suppressing the COX-2/PGE2 signaling [92].  
Consistently, another study has also shown that TSAIII is an effective compound in the Zi-shen pill, which has been demonstrated to inhibit 5-LOX activity. TSAIII can be a ligand of 5-LOX with a specific binding value of 2.919 \(\pm\) 0.296 using affinity ultrafiltration UPLC-MS [93]. The NF-kB signaling pathway, consisting of p65 and p50, has been implicated in most inflammatory responses and natural immunity. Lipopolysaccharide (LPS) can promote the expression and secretion of proinflammatory cytokines, such as IL-1\(\beta\) and TNF\(\alpha\), by activating the TLR/NF-kB signaling pathway, and often results in inflammation [94]. TSAIII is one of the most effective compounds in the _A. asphalodeloides_ extract: it inhibits inflammatory responses and promotes immune effects by suppressing the MAPK and NF-kB signaling pathways in LPS-treated RAW 264.7 cells [95]. In scopolamine-treated neuroblastoma SK-N-SH cells, TSAIII has also shown inhibitory activity against the production of TNF\(\alpha\) and the expression of NF-kB [96].  
It has been reported that TSAIII and the gut microbiota-mediated metabolite sarsasasopgenin exhibit anti-inflammatory effects by inhibiting the activation of NF-kB and MAPK alongside the phosphorylation of IRAK1, TAK1, and IkBa in LPS-treated macrophages. Specifically, TSAIII and sarsasapogenin inhibit the interaction of LPS with its receptor TLR4, with the polarization of M2 to M1 macrophages, the expression of IL-1\(\beta\), TNF\(\alpha\), IL-6, COX-2, and PGE2, which results in the suppression of inflammatory responses [16]. In addition, sarsasapogenin also improves inflammatory responses and insulin resistance in adipose tissues of high fat diet fed obese mice by inhibiting macrophage infiltration. The underlying mechanism of sarsasapogenin in protecting against insulin-resistance-related diseases might be associated with the suppression of IKK/NF-kB and JNK signalingpathways in adipocytes [97]. The ethanol extract of _A. asphalodeloides_, and particularly the saponin-enriched fraction, has demonstrated protective activity against LPS-induced acute lung injury, as shown by a decreased inflammatory cell number in the bronchoalveolar lavage lavage fluid (BALF) and improved histological changes in the lung tissues. TSAIII reduces inflammatory cells in the BALF and decreases the production of proinflammatory cytokines, such as IL-6. Mechanically, TSAIII suppresses the activation of STAT3 but has not been shown to affect the MAPK, NF-kB, and AP-1 signaling pathways [98].