Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells

Lee, Tae-Jin; Kim, Eun Jung; Kim, Shin; Jung, Eun Mi; Park, Jong‐Wook; Jeong, Sang Hoon; Park, Sang Eun; Yoo, Young Hyun; Kwon, Taeg Kyu

doi:10.1158/1535-7163.mct-06-0167

Cited by 95 publications

(75 citation statements)

References 49 publications

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“…Numerous experiments have demonstrated that EVO activated initiator caspases (caspase-8 and 9) and/or effector caspases (caspase-3) to induce the apoptosis in a variety of tumor cell lines including human colorectal carcinoma COLO205 and HT-29 cells (44) and human thyroid cancer cell line ARO (45). In addition, another study showed that EVO promoted translocation of apoptosis-inducing factor (AIF) into the nucleus of human leukemia u937 cells (46). Collectively, EVO was found to induce the apoptosis of many tumor cell lines via caspase-dependent and caspase-independent signaling pathways (47).…”

Section: Discussionmentioning

confidence: 99%

Evodiamine inhibits the proliferation of human osteosarcoma cells by blocking PI3K/Akt signaling

Meng

Shu

et al. 2015

Oncology Reports

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Abstract. Osteosarcoma (OS) is the most common non-hematologic primary malignancy of bone, and multiple chemotherapeutic agents have been applied in the treatment of OS for over 40 years. Nevertheless, due to the poor prognosis of OS, it is essential to develop a novel treatment strategy. Evodiamine (EVO), a quinolone alkaloid extracted from the fruit of Evodia rutaecarpa, has been demonstrated to inhibit tumor cell proliferation. Thus, the main aim of the present study was to investigate the anti-proliferative and apoptosis-inducing effects of evodiamine (EVO) on human OS 143B cells, but also the possible mechanisms underlying these effects. The results of crystal violet staining, flow cytometry, western blot analysis and an in vivo experiment demonstrated that EVO exhibits significant inhibitory effects on cell proliferation, exhibits apoptosis-inducing effects and arrests the cell cycle in 143B cells. According to our findings of polymerase chain reaction (PCR), western blot analysis and recombinant adenoviral transfection, we confirmed that EVO upregulates both the protein and gene levels of phosphatase and tensin homolog (PTEN) in a concentration-dependent manner in 143B cells. Overexpression of PTEN reinforced the anti-proliferative effect of EVO in the 143B cells, while knockdown of PTEN upregulated PI3K/Akt signaling transduction and reversed the inhibitory effect of EVO on 143B cell proliferation. Further analysis indicated that EVO upregulated the expression of PTEN by inactivating PI3K/Akt signaling by decreasing phosphorylated Akt1/2. Based on the above results, we conclude that PTEN/PI3K/Akt signaling is involved in the inhibitory effect on human OS 143B cell proliferation by EVO.

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Section: Discussionmentioning

confidence: 99%

Evodiamine inhibits the proliferation of human osteosarcoma cells by blocking PI3K/Akt signaling

Meng

Shu

et al. 2015

Oncology Reports

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“…In particular, the cytotoxicity of evodiamine and rutaecarpine on various human cancer cell lines has been extensively studied (Ogasawara at al., 2001;Fei et al, 2003;Liao et al, 2005;Xu et al, 2006;Adams et al, 2007). It has been reported that evodiamine inhibited the proliferation of a wide variety of tumor cells by inducing apoptosis via different mechanisms, including caspase-dependent and -independent pathways, the sphingomyelin pathway, and PI3K/Akt/caspase and Fas-L/NF-kB signaling pathways (Lee et al, 2006a;Kan et al, 2007;Wang et al, 2010;Huang et al, 2011). More recently, highly potent evodiamine derivatives were discovered as novel antitumor agents by systemic structure-activity relationship analysis and biologic evaluations (Dong et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Activation of the Indoloquinazoline Alkaloids Evodiamine and Rutaecarpine by Human Liver Microsomes: Dehydrogenation and Inactivation of Cytochrome P450 3A4

et al. 2014

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Evodiamine and rutaecarpine are the main active indoloquinazoline alkaloids of the herbal medicine Evodia rutaecarpa, which is widely used for the treatment of hypertension, abdominal pain, angina pectoris, gastrointestinal disorder, and headache. Immunosuppressive effects and acute toxicity were reported in mice treated with evodiamine and rutaecarpine. Although the mechanism remains unknown, it is proposed that metabolic activation of the indoloquinazoline alkaloids and subsequent covalent binding of reactive metabolites to cellular proteins play a causative role. Liquid chromatography-tandem mass spectrometry analysis of incubations containing evodiamine and NADPH-supplemented microsomes in the presence of glutathione (GSH) revealed formation of a major GSH conjugate which was subsequently indentified as a benzylic thioether adduct on the C-8 position of evodiamine by NMR analysis. Several other GSH conjugates were also detected, including conjugates of oxidized and demethylated metabolites of evodiamine. Similar GSH conjugates were formed in incubations with rutaecarpine. These findings are consistent with a bioactivation sequence involving initial cytochrome P450-catalyzed dehydrogenation of the 3-alkylindole moiety in evodiamine and rutaecarpine to an electrophile 3-methyleneindolenine. Formation of the evodiamine and rutaecarpine GSH conjugates was primarily catalyzed by heterologously expressed recombinant CYP3A4 and, to a lesser extent, CYP1A2 and CYP2D6, respectively. It was found that the 3-methyleneindolenine or another reactive intermediate was a mechanism-based inactivator of CYP3A4, with inactivation parameters K I = 29 mM and k inact = 0.029 minute 21, respectively. In summary, these findings are of significance in understanding the bioactivation mechanisms of indoloquinazoline alkaloids, and dehydrogenation of evodiamine and rutaecarpine may cause toxicities through formation of electrophilic intermediates and lead to drug-drug interactions mainly via CYP3A4 inactivation.

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“…It has been being used for the treatment of gastrointestinal disorders, headache and postpartum hemorrhage (5)(6)(7). Evodiamine is a naturally occurring quinolone alkaloid found in the fruit of Evodia rutaecarpa.…”

Section: Introductionmentioning

confidence: 99%

“…Evodiamine is a naturally occurring quinolone alkaloid found in the fruit of Evodia rutaecarpa. The data of several studies concerning its cytotoxic activity in cancer cells demonstrated that evodiamine inhibited the growth of a wide variety of tumor cells, including breast (8), thyroid (9), liver (10), prostate (11)(12)(13)(14), leukemic T-lymphocyte (5,15), melanoma (6,(16)(17)(18) cervical (19,20), colon (21)(22)(23)(24), colorectal (25) and lung cells (26) through induction of apoptosis, regulation of cell cycle and reduction of invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy

2012

Oncol Rep

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Abstract. Evodiamine, an alkaloid isolated from Evodia rutaecarpa, possesses potent anticancer activity. Although many reports have elucidated the cytotoxic effects of evodiamine in a variety of cancer cells, little is known about the mechanism of evodiamine-induced cytotoxic activity in gastric cancer cells. To date, no report has addressed the synchronized role of autophagy and apoptosis in evodiamineinduced cytotoxic activity. This study was conducted to investigate the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity on SGC-7901 human gastric adenocarcinoma cells and further to elucidate the underlying molecular mechanisms. The MTT assay was used to examine the cytotoxicity of evodiamine against SGC-7901 gastric adenocarcinoma cells. The effects of evodiamine on the cell cycle and apoptosis were measured by flow cytometry and cellular morphology was observed under a phase contrast microscope. Acridine orange (AO) staining was used to detect autophagy. The expression levels of Bcl-2 and Bax were detected by Western blotting. The expression level of Beclin-1 in SGC-7901 cells was monitored by reverse transcription-polymerase chain reaction (RT-PCR). Here, we found that evodiamine significantly inhibited the proliferation of SGC-7901 cells and induced G2/M phase cell cycle arrest. Furthermore, both autophagy and apoptosis were activated during the evodiamine-induced death of SGC-7901 cells. Evodiamine-induced autophagy is partially involved in the death of SGC-7901 cells which was confirmed by using the autophagy inhibitor 3-methyladenine (3-MA). Additionally, Beclin-1 is involved in evodiamine-induced autophagy and the pro-apoptotic mechanisms of evodiamine may be associated with down-regulation of Bcl-2 and up-regulation of Bax expression. The inhibitory effects on SGC-7901 cells were associated with apoptosis, autophagy and cell cycle arrest at the G2/M phase in a dose-dependent manner. These results suggest that evodiamine is an effective natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combined antitumor therapies.

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Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells

Abstract: Evodiamine is one of the major bioactive compounds that have been isolated and purified from the fruit of Evodiae fructus.

Cited by 95 publications

References 49 publications

Evodiamine inhibits the proliferation of human osteosarcoma cells by blocking PI3K/Akt signaling

Evodiamine inhibits the proliferation of human osteosarcoma cells by blocking PI3K/Akt signaling

Metabolic Activation of the Indoloquinazoline Alkaloids Evodiamine and Rutaecarpine by Human Liver Microsomes: Dehydrogenation and Inactivation of Cytochrome P450 3A4

Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy

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