Evodiamine, a Novel NOTCH3 Methylation Stimulator, Significantly Suppresses Lung Carcinogenesis in Vitro and in Vivo

Abstract

Lung cancer is a leading cause of cancer-related deaths worldwide. NOTCH3 signaling is mainly expressed in non-small cell lung carcinoma (NSCLC), and has been proposed as a therapeutic target of NSCLC. While, few agents for preventing or treating NSCLC via targeting NOTCH3 signaling are used in modern clinical practice. Evodiamine (EVO), an alkaloid derived from Euodiae Fructus, possesses low toxicity and has long been shown to exert anti-lung cancer activity. However, the underlying anti-lung cancer mechanisms of EVO are not yet fully understood. In this study, we explored the involvement of NOTCH3 signaling in the anti-lung cancer effects of EVO. Urethane-induced lung cancer mouse model and two NSCLC cell models, A549 and H1299, were used to evaluate the in vivo and in vitro anti-lung cancer action of EVO. A DNA methyltransferase inhibitor was employed to investigate the role of NOTCH3 signaling in the anti-lung cancer effects of EVO. Results showed that EVO potently reduced tumor size and tumor numbers in mice, and inhibited NOTCH3 in the tumors. EVO also dramatically reduced cell viability, induced G2/M cell cycle arrest, inhibited cell migration and reduced stemness in cultured NSCLC cells. Mechanistic studies showed that EVO potently inhibited NOTCH3 signaling by activation of DNMTs-induced NOTCH3 methylation. Importantly, inhibition of NOTCH3 methylation in NSCLC cells diminished EVO’s anti-NSCLC effects. Collectively, EVO, a novel NOTCH3 methylation stimulator, exerted potent anti-lung cancer effects partially by inhibiting NOTCH3 signaling. These findings provide new insight into the EVO’s anti-NSCLC action, and suggest a potential role of EVO in lung cancer prevention and treatment.

BMP9 mediates the anticancer activity of evodiamine through HIF‑1α/p53 in human colon cancer cells

“…In the present study, the effective anticancer activity of Evo, which may be mediated by BMP9 via the upregulation of HIF-1α to partly increase the activity of p53, was demonstrated in human colon cancer. It has been reported that Evo exhibits great anti-cancer activities in many types of cancer, such as tongue, breast, colon, prostate and lung cancer (9)(10)(11)(12)26,27). As far as colon cancer is concerned, the anticancer activity of Evo may be mediated by inactivating the NF-κB (9) or TGF-β1 (11), or activating the p53/p21/Rb pathway (12).…”

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives

“…Further, the proliferation inhibition in A549 cells was induced by evodiamine, which was linked with the ability of evodiamine to increase the expression of oncoprotein metadherin, promote oxidative injury, arrest the cell cycle, and regulate the tumor-associated genes expression by controlling protein kinase B/ nuclear factor-κB (AKT/NF-κB) and sonic hedgehog/GLI family zinc finger 1 (SHH/GLI1) pathways [ 30 , 31 ]. Su et al (2018) reported that evodiamine activate DNA methyltransferase 3A (DNMT3A)-induced neurogenic locus notch homolog protein 3 (NOTCH3) methylation, and subsequently induced growth inhibition in both A549 and H1299 NSCLC cells [ 32 ]. Moreover, the cytoprotective autophagy was induced by evodiamine in Lewis lung carcinoma (LLC) cells, and the combination of evodiamine with autophagy inhibitor therapy increased cell chemosensitivity [ 33 ].…”

Evodiamine Induces Apoptosis in SMMC-7721 and HepG2 Cells by Suppressing NOD1 Signal Pathway

“…Evodia rutaecarpa Bentham is a traditional herbal medicine commonly used in Asia as an analgesic, anti-emetic, hemostatic, anti-hypertensive, and uterotonic agent [ 39 ]. Evodiamine, an active ingredient isolated from the fruit of Evodia rutaecarpa Bentham , has been well documented to inhibit the proliferation of various human cancer cells [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Previous study has shown that Evo could also change the morphology and decrease viability and proliferation of renal carcinoma cells [ 40 ].…”

“…Evo inhibited growth of human colorectal carcinoma cells by increasing expression of Bax and p53 and decreasing expression of Bcl-2 [ 42 ]. Evo induced G2/M cell cycle arrest and decreased expression of CyclinB1 and cdc2 in lung cancer [ 16 ]. Evo also induced G2/M arrest and apoptosis in H446 and H1688 human small-cell lung cancer cells [ 43 ].…”

“…Evodiamine (Evo), an active ingredient isolated from the fruit of Evodia rutaecarpa Bentham, has diverse well-defined biological activities including anti-obesity, anti-inflammation, and anti-tumor effects [ 10 , 11 , 12 , 13 , 14 ]. Researchers have found that Evo can induce apoptosis in human ovarian cells, lung carcinogenesis, pancreatic cancer, breast cancer, human melanoma cancer, thyroid cancer, human bladder cancer, human leukemia, colon cancer, and hepatocellular cancer [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Among them, antitumor activities through the suppression of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) activation have been extensively investigated [ 15 , 20 , 25 ].…”