Evodiamine Research Articles

Evodiamine Stabilizes Topoisomerase I-DNA Cleavable Complex to Inhibit Topoisomerase I Activity

Evodiamine (EVO), an alkaloidal compound isolated from Evodia rutaecarpa (Juss.), has been reported to affect many physiological functions. Topoisomerase inhibitors have been developed in a variety of clinical applications. In the present study, we report the topoisomerase I (TopI) inhibitory activity of EVO, which may have properties that lead to improved therapeutic benefits. EVO is able to inhibit supercoiled plasmid DNA relaxation catalyzed by TopI. Upon treatment 0~10 μM EVO TopI was depleted in MCF-7 breast cancer cells in a concentration-dependent and time-dependent manner in 0~120 min. A K-SDS precipitation assay was performed to measure the extent of Top I-trapped chromosomal DNA. The ability of EVO to cause the formation of a TopI-DNA complex increased in a concentration-dependent manner, in that the DNA trapped increased by 24.2% in cells treated with 30 μM. The results suggest that EVO inhibits TopI by stabilizing the enzyme and DNA covalent complex.

The permeability and the efflux of alkaloids of the Evodiae fructus in the Caco‐2 model

The intestinal transport of four indoloquinazoline alkaloids, rutaecarpine (RCP), evodiamine (EDM), dehydroevodiamine (DEDM) and wuzhuyurutine B (WZYB) isolated from the Evodiae fructus was investigated using the monolayers of the human colon adenocarcinoma cell line Caco-2 as a model system for intestinal absorption. The four alkaloids were measured by high performance liquid chromatography (HPLC) coupled with UV detector. Transport parameters and permeability coefficients were then calculated and compared under identical conditions with those of mannitol, propranolol and paclitaxel. Permeability coefficients were also compared with the reported values for model compounds like propranolol and mannitol. The four alkaloids at a concentration of 5 microM were demonstrated substantial transport across the Caco-2 cell monolayers with moderate to high permeability coefficients and WZYB demonstrated higher-level intestinal transcellular efflux. The transports of DEDM and WZYB were concentration dependent at the concentrations of 5-25 microM. Among four alkaloids, EDM and DEDM are better-transported compounds, and RCP and WZYB are moderate transport compounds. The data support the involvement for multidrug resistance-associated proteins (MRPs) in the intestinal transcellular efflux of WZYB.

Anti‐proliferative effects of evodiamine on human prostate cancer cell lines DU145 and PC3

Prostate carcinoma is one of the most common malignant tumors and has become a more common cancer in men. Previous studies demonstrated that evodiamine (EVO) exhibited anti-tumor activities on several cancers, but its effects on androgen-independent prostate cancer are unclear. In the present study, the action mechanisms of EVO on the growth of androgen-independent prostate cancer cells (DU145 and PC3 cells) were explored. EVO dramatically inhibited the growth and elevated cytotoxicity of DU145 and PC3 cells. The flow cytometric analysis of EVO-treated cells indicated a block of G2/M phase and an elevated level of DNA fragmentation. The G2/M arrest was accompanied by elevated Cdc2 kinase activity, an increase in expression of cyclin B1 and phosphorylated Cdc2 (Thr 161), and a decrease in expression of phosphorylated Cdc2 (Tyr 15), Myt-1, and interphase Cdc25C. TUNEL examination showed that EVO-induced apoptosis was observed at 72 h. EVO elevated the activities of caspase 3, 8, and 9 in DU145 cells, while in PC3 cells only the activities of caspase 3 and 9 were elevated. EVO also triggered the processing of caspase 3 and 9 in both DU145 and PC3 cells. We demonstrate that roscovitine treatment result in the reversion of G2/M arrest in response to EVO in both DU145 and PC3. However, inhibitory effect of roscovitine on EVO-induced apoptosis could only be observed in DU145 rather than PC3. In DU145, G2/M arrest might be a signal for initiation of EVO-triggered apoptosis. Whereas EVO-triggered PC3 apoptosis might be independent of G2/M arrest. These results suggested that EVO inhibited the growth of prostate cancer cell lines, DU145 and PC3, through an accumulation at G2/M phase and an induction of apoptosis.

Thermoregulatory effects of alkaloids isolated from Wu-chu-yu in afebrile and febrile rats

Dehydroevodiamine (DeHE) and evodiamine (EVO), alkaloids isolated from a Chinese medicinal herb, Wu-chu-yu, exhibit calcium antagonistic activity. Intraperitoneal injections of DeHE (5–20 mg/kg) and EVO (2.5–10 mg/kg) caused a dose-related hypothermia in afebrile rats at an ambient temperature (Ta) of 20 °C. Because the heat production of alkaloid-injected rats did not differ from that of the controls, the hypothermic effect likely resulted from increased peripheral heat loss. This suggestion is supported by the finding that both DeHE and EVO did not affect the thermoregulatory response of rats exposed to a Ta of 35 °C, at which heat loss was maximized. Injection of the same doses of DeHE and EVO attenuated the febrile response in a dose-related manner, induced by intrahypothalamic injection of exogenous pyrogen. The attenuation of the febrile response was associated with a reduction in heat production. Because DeHE and EVO did not affect HP in afebrile rats at a Ta of either 20 or 35 °C, but suppressed the metabolic rate of febrile rats at 20 °C, the thermoregulatory effect of DeHE and EVO could involve both a calcium-dependent increase in heat loss and a suppression in heat production; the latter may only be manifested when the set point for thermoregulation is elevated.

A New Approach to Quinazolinocarboline Alkaloids: Synthesis of (±)-Evodiamine, Rutaecarpine and Dehydroevodiamine

A New Approach to Quinazolinocarboline Alkaloids: Synthesis of (±)-Evodiamine, Rutaecarpine and Dehydroevodiamine