**4. Potential NCE to Target EMT**

#### *4.1. Artemisinin (ATM)*

ATM is a sesquiterpene lactone isolated from sweet, warm wood, *Artemisia annua.* It is an antimalarial agent to treat multidrug-resistant *falciparum malaria* strains, mediated by producing organic peroxides [59]. ATM also has potent anti-cancer activity against CRC, BC, gastric cancer (GC), and cervix cancer (CC). Its anti-carcinogenic action is similar to antimalarial action in that free iron cleaves its endoperoxide bridge, releasing free radicals that cause cytotoxicity. ATM's low toxicity and high specificity for cancer cells led to its development as an anti-cancer molecule. Dihydroartemisinic acid (DHA), an ATM derivative, reduced inflammation in a rat arthritis model by downregulating Interleukin-6 (IL-6). Additionally, DHA has anti-cancer properties. It can induce apoptosis in leukemic cells via noxa-mediated mechanisms [60].

Moreover, it inhibits GC cell invasion, migration, and proliferation by inhibiting the activation of phosphoinositide 3-kinase/protein kinase B and SNAIL. According to Sun et al., DHA's anti-inflammatory and anti-cancer activities are mediated via microRNAs (miRNAs). DHA, for example, inhibits inflammation in vascular smooth muscle cells by regulating the miR-376b-3p/KLF pathway. The Jumonji and AT-rich interactive domain2 (ARID-2)/miR-7/miR-34a pathway inhibit prostate cancer cells by downregulating AXL tyrosine. In laryngeal cancer, miRNAs, in particular, play a function in EMT. For example, miR-217 inhibits EMT while miR-10b promotes it. miR-130b-3p is a tumor suppressor because it inhibits laryngeal cancer development, angiogenesis, migration, and invasion [61]. FoxM1, a member of the conserved forkhead box transcription factor family, is involved in cell cycle regulation, DNA damage repair, and apoptosis and has been associated with the development of breast, pancreas, and liver carcinomas. Nandi et al. hypothesized that FoxM1 was a critical inhibitory target of ATM in hepatocellular carcinoma (HCC) and that FoxM1 may play a role in the cell cycle triggered by DHA ATM-inhibited HCC cell survival and proliferation by attenuating FoxM1 and its transcription targets and interfering with FoxM1 trans-activation [62].

#### *4.2. Strychnine/Brucine*

Brucine is an alkaloid related to strychnine obtained from the *Strychnic Nux-vomica* tree. It has analgesic, anti-cancer, anti-inflammatory, antioxidant, and anti-venom properties [63]. In vitro, it inhibits the proliferation of Hela and K562 cell lines. Brucine also showed anti-metastasis action in MDA-MB-231 and Hs578-T-cells and inhibited invasive capacity and adhesion of MDA-MB-231 and Hs578-T-cells Matrigel, and preventing mRNA of Ecadherin, catenin, VIM, FN1, MMP-2, and MMP-9 in MDA-MB-231 cells [64]. These data collectively suggest that brucine might be a potential anti-cancer molecule; in vivo studies are still needed to confirm its anti-cancer potential.
