Amelioration of AOM/DSS-Induced Murine Colitis-Associated Cancer by Evodiamine Intervention is Primarily Associated with Gut Microbiota-Metabolism-Inflammatory Signaling Axis

Evodiamine (EVO), an indole alkaloid derived from Rutaceae plants Evodia rutaecarpa (Juss.) Benth.、Evodia rutaecarpa (Juss.) Benth. Var. bodinieri (Dode) Huang or Evodia rutaecarpa (Juss.) Benth. Var. officinalis (Dode) Huang, has anti-inflammatory and anti-tumor activities. Our previous study found that EVO attenuates colitis by regulating gut microbiota and metabolites. However, little is known about its effect on colitis-associated cancer (CAC). In this study, the protective effects of EVO on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and tumor mice were observed, and the underlying potential mechanism was clarified. The results suggested that EVO ameliorated AOM/DSS-induced colitis by inhibiting the intestinal inflammation and improving mucosal barrier function. And EVO significantly reduced the number and size of AOM/DSS-induced colorectal tumors along with promoted apoptosis and inhibited proliferation of epithelial cell. Moreover, EVO promoted the enrichment of SCFAs-producing bacteria and reduced the levels of the pro-inflammatory bacteria, which contributes to the changes of microbiota metabolism, especially tryptophan metabolism. Furthermore, inflammatory response (like Wnt signaling pathway、Hippo signaling pathway and IL-17 signaling pathway) were effectively alleviated by EVO. Our study demonstrated that the protective therapeutic action of EVO on CAC is to inhibit the development of intestinal inflammation-cancer by regulating gut microbiota metabolites and signaling pathways of colon intestinal epithelial, which may represent a novel agent for colon cancer prevention via manipulation of gut microbiota.

The Synthesis, Structural Modification and Mode of Anticancer Action of Evodiamine: a review

Background: Finding novel antitumor reagents from naturally occurring alkaloids is a widely accepted strategy. Evodiamine, a tryptamine indole alkaloid isolated from Evodia rutaecarpa, has a wide range of biological activities, such as antitumor, anti-inflammation, and anti-bacteria. Hence, research works on the structural modification of evodiamine will facilitate the discovery of new antitumor drugs. Objective: The recent advances in the synthesis of evodiamine, and studies on the drug design, biological activities, and structure-activity-relationships of its derivatives, published in patents and primary literatures, are reviewed in this paper. Methods: The literatures, including patents and follow-up research papers from 2015 to 2020, related to evodiamine is searched in the Scifinder, PubMed, Espacenet, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The key words are evodiamine, synthesis, modification, anticancer, mechanism. Results: The synthesis of evodiamine are summarized. Then, structural modifications of evodiamine are described, and the possible modes of actions are discussed. Conclusion: Evodiamine has a 6/5/6/6/6 ring system, and the structural modifications are focused on ring A, D, E, C5, N-13, and N-14. Some compounds show promising anticancer potentials and warrant further study.

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it is important to inhibit the activity or reduce the expression level of ABCB1 to maintain an effective intracellular level of chemotherapeutic drugs. In this study, we found that rutaecarpine, a bioactive alkaloid isolated from Evodia Rutaecarpa, has the capacity to reverse ABCB1-mediated MDR. Our data indicated that the reversal effect of rutaecarpine was related to the attenuation of the protein level of ABCB1. Mechanistically, we demonstrated that ABCB1 is a newly discovered substrate of E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8). MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation. In short, rutaecarpine increased the degradation of ABCB1 protein by upregulating the protein level of MARCH8, thereby antagonizing ABCB1-mediated MDR. Notably, the treatment of rutaecarpine combined with other anticancer drugs exhibits a therapeutic effect on transplanted tumors. Therefore, our study provides a potential chemotherapeutic strategy of co-administrating rutaecarpine with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.

Rutaecarpine Protects against Acetaminophen-Induced Acute Liver Injury in Mice by Activating Antioxidant Enzymes

Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is used to treat hypertension, postpartum hemorrhage, dysentery, and amenorrhea as a traditional medicine in Asia. We investigated the effect of rutaecarpine on acetaminophen-induced hepatotoxicity in mice. Rutaecarpine was administered orally daily for seven consecutive days, followed by intraperitoneal injection of acetaminophen in mice on day seven to induce hepatotoxicity. Rutaecarpine pretreatment significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) activities and hepatic malondialdehyde content and prevented acetaminophen-induced hepatic glutathione depletion. Furthermore, CYP2E1 expression was decreased by rutaecarpine pretreatment in a dose-dependent manner. Rutaecarpine pretreatment inhibited acetaminophen-induced expression of inflammatory cytokines by inhibiting NF-κB activation by JNK1/2. Also, rutaecarpine pretreatment promoted Nrf2-mediated activation of the antioxidant enzymes GCLC, HO-1, and NQO1. This indicates that the protective effect of rutaecarpine during acetaminophen-induced acute liver injury is mediated by the activation of antioxidant enzymes. Therefore, rutaecarpine has a protective effect of APAP-induced liver damage.

Transdermal Delivery of Rhizoma Coptidis and Evodia Rutaecarpa: The Effects of Enhancers on Permeation Across SD Mouse Skin

Background: Oral ulceration is a common, painful condition of uncertain aetiology. Traditional Chinese medicine has good effect. One kind of treatment method is to use rhizoma coptidis, evodia rutaecarpa powder 10g each mixed with vinegar to paste in the foot springs point. The purpose of this study is to convert this prescription into a corresponding preparation for everyone's convenience. Methods: The enhancement effect of a series of different concentrations of fat-soluble azone, water-soluble azone, dimethyl sulfoxides, acetic acid, on the skin permeability of rhizoma coptidis, evodia rutaecarpa powder was studied in vitro by using Franz diffusion cells and SD mouse skin. The concentrations of the main components palmatine hydrochloride, berberine hydrochloride, evodiamine, rutacarpine in the preparation were determined by an HPLC method. Results: The addition of dimethyl sulfoxide, 2-8% w/w water-soluble azone, 8% w/w fat-soluble azone never increased palmatine hydrochloride and berberine hydrochloride flux with respect to the control preparation. The enhancing effects of 45% acetic acid, 1% water-soluble azone and 5% fat-soluble azone were evident on the palmatine hydrochloride and berberine hydrochloride permeability. The target substances evodiamine and rutacarpine were not detected in the receiving solution, and there were residues in the skin, respectively. The amount of evodiamine and rutacarpine residued in the skin obtained from formulations including 45% w/w acetic acid or 5% w/w fat-soluble azone were significantly higher (p<0.05) than that obtained from the blank control formulation. Conclusions: The experimental results revealed that 5% fat-soluble azone transdermal agent has the optimal performance in the rhizoma coptidis, evodia rutaecarpa preparation.