Evodiamine: Bioactive Alkaloid with Anticancer, Metabolic, and Multitarget Therapeutic Potential

The bioactive alkaloid (a naturally occurring amino produced by a plant) extract known as evodiamine comes from a plant called Evodiae Fructus. It's a stimulant that increases your resting core temperature and body heat. Evodiamine is also known as Wu-Chu-Yu, and is used by Chinese herbal specialists as a weight loss supplement. While this isn't backed up by any medical studies, the Chinese have used this for weight loss for centuries. Evodiamine raises your body's temperature and can inhibit the growth of certain cancer cells. It also manipulates your metabolism when combined with certain drugs and influences the secretion of catecholamines from your adrenal glands. Catecholamines are important because they cause physiological changes in your body that prepare your body for a physical response. It's much like having increased adrenaline, your blood pressure, heart rate, and blood glucose levels all increase after taking evodiamine. Additionally, it stimulates the vanilloids in your body and reduces the uptake of fat. In turn, it increases your body's natural rate of burning fat. It's a mild stimulant that has shown to increase positive energy and diuretic characteristics in a body.

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives

Nature derived compounds are important for therapeutic leads. Especially for anti-cancer agents, more than half cancer chemotherapy drugs are natural products and their derivatives. Natural sources often provide privileged skeletons and define novel drug targets. Among which, alkaloids, containing extra nitrogen atoms compared to other natural products, enrich structural diversity and some of them show better drug-like properties, such as drug-protein affinity and bioavailability. Evodiamine is a famous alkaloid with a quinazolinocarboline skeleton. It was isolated from Evodia rutaecarpa, the dried and nearly ripe fruits of Euodia rutaecarpa Benth and E. rutaecarpa Benth var. bodinieri Huang, three plants belonging to the family of Rutaceae. Evodiamine has been traditionally used to cure headache, amenorrhea, postpartum hemorrhage and gastrointestinal disorders. In 2013, Yu et al. summarized the pharmacokinetics and the detailed exploration of target-binding properties of evodiamine. Moreover, a patent review for therapeutic and cosmetic applications of it and its derivatives was reported by Gavaraskar in 2015. In 2016, Tan et al. reviewed the evodiamine functions and mechanisms of action in various chronic diseases. This article updated the review of the antiproliferative activities of evodiamine, and the antiproliferative activities of structurally modified new analogues of it were summarized for the first time.[1]

Less than 15% of all lung cancers are small cell lung cancer (SCLC), and nearly 85% of lung cancer patients were diagnosed as non-small cell lung cancer (NSCLC). In human SCLC NCI-H1688 and NCI-H446 cells, G2/M arrest and the subsequent apoptosis were induced by evodiamine through mitochondria-dependent intrinsic apoptosis pathway rather than death receptor (DR)-induced extrinsic apoptotic pathway. The increased release of cytochrome c to cytosol activated intrinsic apoptotic pathway mediated by activation of caspase-9, -3, while increased release of cytochrome c to nuclear activated extrinsic apoptotic pathway mediated through activation of caspase-8. These studies indicated that evodiamine could induce apoptosis in NSCLC via both intrinsic and extrinsic pathways. It was shown to decrease the expression of vascular endothelial growth factor (VEGF), a potent endothelial cell mitogen, in human lung adenocarcinoma CL1 cells. The conditioned medium derived from CL1 cells induced the formation of tube-like structures by human umbilical vein endothelial cells (HUVECs), while conditioned medium produced from evodiamine-pretreated CL1 cells exerted low ability of inducing capillary tube formation.

Evodiamine as the Active Compound of Evodiae fructus

Prostate cancer remains a huge challenge to men's health worldwide. It is reported that the incidence and mortality of prostate cancer ranks the second in males. The treatments of prostate cancer include radiotherapy, chemotherapy, surgery, and hormonal therapy. Herbal medicine plays a major role in the prevention and treatment of cancers and other diseases worldwide, especially in Asian countries. Inhibiting cancer cell growth and metastasis constitute the major aspects in anticancer strategies. Cell migration is essential for tumor metastasis to colonize remote sites, frequently resulting in cancer deaths. In this study, we identified evodiamine as the active compound of EF through a network pharmacology approach and evaluated the antiproliferative effects of evodiamine on prostate cancer DU145 cells. Nuclear factor kappaB (NF-κB), a transcription factor, translocates to the nucleus to facilitate oncogene transcription after activation in response to various stimuli. Further mechanistic study demonstrated that it induces mitochondrial apoptosis and inhibits migration of prostate cancer cells through PI3K/AKT/NF-κB signaling pathway. This study will provide a rationale for using it as the potential lead drug for prostate cancer treatment. From 5 potential active compounds of EF, evodiamine was verified to possess the most potent cytotoxicity against DU145 cells.[2]

Hence, we suggested that evodiamine is the active compound of EF to inhibit proliferation and migration of prostate cancer through PI3K/AKT signaling pathway. To predict the downstream substrates of AKT, we focused on the transcription factor NF-κB, which is closely related to tumorigenesis and tumor progression. The results of molecular docking demonstrated a good binding affinity between evodiamine and PI3K, as well as evodiamine and AKT. The inhibition of PI3K/AKT/NF-κB by it in vitro was also verified by Western blot. However, it was selected as the most active ingredient of EF against prostate cancer but not the only one. The active ingredients of herbal medicine are multiple and complex. Moreover, the safety concern exists as the precise target of it is unknown and the excessive inhibition of PI3K/AKT/NF-κB pathway may bring about side effects. Hence, evodiamine treatment may be more potent but not necessarily more effective than EF treatment, which needs further evaluation. Currently, a number of novel drug delivery systems have been designed to improve the bioavailability and minimize side effects of low-solubility natural medicines.

Pharmacological Actions of Multi-Target-Directed Evodiamine

Many common diseases like diabetes, cardiovascular disease, and cancer are caused by a set of several factors, such as physiological, pathological, environmental, and lifestyle. In the past, the main effort was aimed at developing highly specific molecules acting on single targets. Growing evidence demonstrates that evodiamine represents an important compound possessing a wide spectrum of biological activities, suggesting that it might interact with a number of diverse targets to carry out its therapeutic effects. The broad spectrum of medicinal properties associated with this compound has encouraged medicinal chemists to design and synthesize a large number of novel therapeutic agents. Several analogues exhibit significant anti-tumour, anti-microbial, and anti-inflammatory activities. For this reason evodiamine is an object of continuously growing interest amongst the scientists. Evodiamine has been shown to exhibit anti-tumor properties by inhibiting proliferation of various cancer cell lines, including cervical cancer cells, colon cancer cells, lung cancer cells, melanoma cells, leukemic T-lymphocyte cells, prostate cancer cells and breast cancer cells.[3]

Identification of molecular targets of evodiamine is an enormous opportunity for modern pharmacology. Up to data, three proteins are believed to be direct targets of evodiamine, including TRPV1, the aryl hydrocarbon receptor (AhR), and topoisomerases I and II. These proteins seem to be important in inflammation, cancer and other diseases. In fact, compounds which can regulate multiple targets may have superior utility over single-target drugs. For example, Guerrant et al. synthesized dual-acting histone deacetylase and topoisomerase II inhibitors, which potently inhibit the proliferation of representative cancer cell lines.

References

[1]Hu, Xu et al. “Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives.” International journal of molecular sciences vol. 19,11 3403. 30 Oct. 2018, doi:10.3390/ijms19113403

[2]Lei Y, Chan M, Liu H, Lyu W, Chen L, Zhong Y, Gan H, Wang M, Qi M, Guo Y, Liu J, Zhang E. Evodiamine as the Active Compound of Evodiae fructus to Inhibit Proliferation and Migration of Prostate Cancer through PI3K/AKT/NF-κB Signaling Pathway. Dis Markers. 2022 Jul 18;2022:4399334. doi: 10.1155/2022/4399334. PMID: 35899176; PMCID: PMC9313987.

[3]Yu H, Jin H, Gong W, Wang Z, Liang H. Pharmacological actions of multi-target-directed evodiamine. Molecules. 2013 Jan 31;18(2):1826-43. doi: 10.3390/molecules18021826. PMID: 23434865; PMCID: PMC6270287.