*4.5. Polyphyllin 1*

Polyphyllin 1 (PP 1) demonstrated its anti-cancer activity via its apoptotic action and several pathways effectively against various cancers. Polyphyllin I induces apoptosis in HepF-2-Cells, and neural progenitor cells (NPC) cell lines [73]. The natural herb Paris polyphylla makes PP1 and has anti-cancer properties against various malignancies, including drug-resistant tumors. Paris polyphylla was recently found to inhibit CRC cells by activating autophagy and improving the efficiency of chemotherapy (Doxorubicin). By decreasing CIP2A/PP2A/Akt signaling, PP1 also reduced cisplatin-resistant GC cells. Liu et al. demonstrated that PP 1 has potent anti-cancer action on human non-small cell lung cancer (NSCLC) mediated by CHOP stabilization. PP1 induces ROS, and ER stress inhibits unfolded protein response (UPR) in cancer cells, subsequently increasing the levels of CHOP Via, accelerating CHOP gene expression. The UPR chaperone GRP78, restrained by PP1, is the main mechanism for CHOP stabilization [74].

#### *4.6. Paeoniflorin (PF)*

Paeoniflorin (PF) is a monoterpene glycoside derived from the root of *Paeonia lactiflora*. In the past, this plant's roots were utilized in eastern medicine for pain, muscle spasms, inflammation, menstruation dysfunction, and degenerative illnesses for a long time [75–78]. Studies indicated that PF inhibits tumor growth, invasion, and metastasis in vivo and in vitro. In hypoxia-induced EMT in MDA-MB-231 BC cells, PF treatment resulted in a considerable increase in E-cadherin levels and a drop in CDH2 and Vimentin levels in the cells. Subsequently, it suppressed the EMT process by altering the expression of HIF-1, which is involved in hypoxia-driven EMT [79]. The hippo pathway plays a significant role in the progression of GC. This pathway is said to be dysregulated and thus contributes to gastric oncology and metastasis. Two important factors, yes associated protein (YAP1) and Transcriptional coactivator with PDZ-binding motif (TAZ), produce their metastatic effect via crosslinking with Notch, TGF-β, and Wnt/ β-catenin in GC. In GC, PF exerts its anti-cancer effect via regulation of the hippo signaling pathway and downregulating the effect of TAZ [80]. Further, there is a need to explore its potential in other cancers.

#### *4.7. Halicondramine*

Halicondramine (HCA) is a trisoxazole-containing macrolide from the marine sponge Chondrosia corticata [81]. It possesses antifungal and cytotoxic properties. It also has anti-proliferative activity against cancerous cells [82,83]. Modulation of the EMT is a key target for their action. Treatment with HCA significantly reduced the expression of MMP2 and 9, and CDH2. On the contrary, E-cadherin expression was significantly increased. HCA also inhibits the expression of PRL-3, a metastasis-associated marker, and PI3 kinase

subunits p85 and p110 (PRL-3's downstream targets). These findings imply that HCA inhibits EMT in human adenocarcinoma prostate cancer cells by modulating PRL-3 and downstream targets, such as PI3 kinase [48].

#### *4.8. Ligustrazine*

Ligustrazine (LSZ) is obtained from the rhizome of *Ligusticum wallichii* [84]. LSZ is shown to have anti-inflammatory, anti-fibrotic, antioxidant activity, and tumor-suppressing properties in numerous cancers, including LC, GC, BC, and melanoma [85]. LSZ showed anti-proliferative and anti-metastatic action [6]. LSZ increased E-cadherin expression while decreasing the mesenchymal indicators CDH2 and VIM expression. LSZ inhibits EMT in SK-OV-3 cells via modulating miR-211 expression [86].

#### *4.9. Fucoidan*

The Fucoidan (FC) is a polysaccharide obtained from brown seaweeds and has shown anti-proliferative action on BC cells, such as 4T1 and MDA-MB-231. It also lowered metastatic lung nodules in female Balb/c mice with 4T1 xenografts. The TGFRs molecular network is critical in controlling EMT in cancer cells. It was observed that FC efficiently reverses TGFR-induced EMT morphological alterations, increases epithelial markers, decreases mesenchymal markers and transcriptional repressor expression Twist, Snail, and Slug. Furthermore, fucoidan suppresses migration and invasion during EMT, implying that TGFR-mediated signaling is involved in BC cells [87].
