Abstract
Evodiamine (EVO; 8,13,13b,14-tetrahydro-14-methylindolo[2′3′-3,4]pyrido[2,1-b]quinazolin-5-[7H]-one derived from the traditional herbal medicine Evodia rutaecarpa was reported to possess anticancer activity; however, the anticancer mechanism is still unclear. In this study, we investigated the anticancer effects of EVO on human colon COLO205 and HT-29 cells and their potential mechanisms. MTT and lactate dehydrogenase (LDH) release assays showed that the viability of COLOL205 and HT-29 cells was inhibited by EVO at various concentrations in accordance with increases in the percentage of apoptotic cells and cleavage of caspase-3 and poly(ADP ribose) polymerase (PARP) proteins. Disruption of the mitochondrial membrane potential by EVO was accompanied by increased Bax, caspase-9 protein cleavage, and cytochrome (Cyt) c protein translocation in COLO205 and HT-29 cells. Application of the antioxidant N-acetyl-L-cysteine (NAC) inhibited H2O2-induced reactive oxygen species (ROS) production and apoptosis, but did not affect EVO-induced apoptosis of COLO205 or HT-29 cells. Significant increases in the G2/M ratio and cyclinB1/cdc25c protein expression by EVO were respectively identified in colon carcinoma cells via a flow cytometric analysis and Western blotting. Induction of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) protein phosphorylation was detected in EVO-treated cells, and the JNK inhibitor, SP600125, but not the ERK inhibitor, U0126, inhibited EVO-induced phosphorylated JNK protein expression, apoptosis, and G2/M arrest of colon carcinoma cells. Data of the structure-activity analysis showed that EVO-related chemicals containing an alkyl group at position 14 were able to induce apoptosis, G2/M arrest associated with increased DNA ladder formation, cleavage of caspase-3 and PARP, and elevated cycB1 and cdc25c protein expressions in COLO205 and HT-29 cells. Evidence supporting JNK activation leading to EVO-induced apoptosis and G2/M arrest in colon carcinoma cells is provided, and alkylation at position 14 of EVO is a critical substitution for treatment of colonic cancer.
Highlights
Colorectal cancer (CRC) is the second leading diagnosed cancer with high mortality, and remains a significant global health problem [1,2]
EVO reduced the viability of colorectal carcinoma cells via apoptosis induction In order to examine the effect of EVO on the viability of two colon carcinoma cells COLO205 and HT-29, MTT and Lactate dehydrogenase (LDH) release assays were applied in the present study
Examination of apoptotic proteins including caspase-3 and PARP protein expressions showed that increased cleavage of caspase-3 and PARP proteins was detected in COLO205 and HT-29 cells under EVO stimulation (Fig. 1E)
Summary
Colorectal cancer (CRC) is the second leading diagnosed cancer with high mortality, and remains a significant global health problem [1,2]. Many therapeutic strategies such as surgery and chemotherapy are used to treat CRC; there are troublesome side effects with chemotherapy, and surgical treatment is associated with high mortality and local recurrence [3,4]. In addition to anti-tumor effect, EVO may inhibit insulin-Stimulated mTOR-S6K activation in adipocytes and improves glucose tolerance in Obese/Diabetic Mice [11]. These results reveals the beneficial effects of EVO, the mechanism underlying its antitumor activities and the structure-activity relationship of EVO are still poorly defined
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