Evodiamine inhibits stemness and metastasis by altering the SOX9–β‐catenin axis in non‐small‐cell lung cancer

Abstract

Evodiamine (EVO), a natural dietary alkaloid extracted from the roots of the Evodia rutaecarpa, has shown anticancer activities. Here, we have investigated EVO's role in inhibiting cell proliferation and migration in A549 and NCI‐H522 lung cancer cells. EVO decreased the cell viability in A549 and NCI‐H522 cells in a dose‐ and time‐dependent manner. It also induced apoptosis by downregulating the expression of antiapoptotic Bcl‐2 and upregulating the expression of cleaved caspase‐3 and PARP. In addition, the treatment of EVO elevated the level of reactive oxygen species (ROS) generation inside the cells to induce the cell death pathways. In contrast, the pretreatment of ROS scavenger, N‐acetyl cysteine, reverses the effect of EVO and attenuates cell death. Moreover, excess ROS generation in response to EVO resulted in the depletion of mitochondrial membrane potential. Furthermore, it induced DNA damage and arrested the cell cycle at the G2/M phase in A549 and NCI‐H522 cells. Our study also investigated that EVO significantly suppressed tumorigenicity by inhibiting colony formation and tumorsphere formation. However, the treatment of EVO downregulated the cancer stem cell markers CD44 and CD133 in non‐small‐cell lung cancer. The inhibitory effect of EVO on cell invasion was mediated by altering the expression of E‐cadherin, ZO‐1, N‐cadherin, and Vimentin. Additionally, we have revealed that EVO treatment showed downregulation of SOX9, an upstream component of β‐catenin. Lastly, we have demonstrated that EVO targets the SOX9–β‐catenin axis by reducing SOX9 and β‐catenin expression. These findings suggested that EVO could be a promising agent for treating human lung cancer.

Folate Functionalized and Evodiamine‐Loaded Pluronic Nanomicelles for Augmented Cervical Cancer Cell Killing

“…It is well known that Evo exerts anticancer effects via induction of apoptosis in various cancer cells. [ 62,63 ] HeLa cells treated with Evo and ENM display yellowish green, orange, and orange–red fluorescence implies early apoptotic, late apoptotic, and necrotic induction in the cells, respectively. Compared to Evo, ENM manifested more potent apoptosis, which is possibly due to higher uptake of ENM into tumor cells and produced higher cytotoxicity than pure drug.…”

A systematic and comprehensive analysis of T cell exhaustion related to therapy in lung adenocarcinoma tumor microenvironment

“…However, other pathways and TEX pathways are still worthy of further exploration in LUAD. Subsequent immune checkpoint analysis revealed that the high risk group had increased expression of CD44 , a stemness marker of non-small cell lung cancer, and activation of CD44 related pathways promoted squamous cell lung cancer resistance to FGFR1 inhibition ( Elakad et al, 2022 ; Panda and Biswal, 2022 ). These results suggest that TEX may be involved in the stemness and other phenotypes of LUAD resulting in a poorer prognosis in high-risk patients.…”

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“…Evodiamine, a key active ingredient of the fruit of Evodia rutaecarpa, has been demeonstrated anti-tumor activity in a variety of tumor cells, including colon (Kim et al, 2019;F. S. Li et al, 2020), lung (Jiang et al, 2020;Panda & Biswal, 2022), osteosarcoma (S. Yang et al, 2020;Zhou & Hu, 2018), breast (Du et al, 2017), hepatocellular (Guo et al, 2018), pancreatic (Hong et al, 2020) and prostate cancer cells (Cheng et al, 2022;Lei et al, 2022). The anti-tumor mechanism of evodiamine in gastric cancer cells may include inhibiting PTEN-mediated EGF/PI3K (R. Yang et al, 2021) and inhibiting FAK/AKT/mTOR (J. Y.…”

“…And in the fruit of evodia rutaecarpa, the main effective component is evodiamine (EVO), a quinolone alkaloid that involves a variety of biological functions (D. Li, Li, Jiang, Liu, & Zhao, 2022). Some previous studies demonstrated that EVO is endowed with several antitumor effects which may include inducing inhibition of proliferation and metastasis, G2/M arrest and cell apoptosis (Hwang et al, 2020;Panda & Biswal, 2022;J. Y. Yang, Woo, Lee, & Kim, 2022;R.…”