title: ETME, a novel β-elemene derivative, synergizes with arsenic trioxide in inducing apoptosis and cell cycle arrest in hepatocarcinoma cells via a p53-dependent pathway.
abstract: Arsenic trioxide (ATO) has been identified as an effective treatment for acute promyelocytic leukemia (APL) but is much less effective against solid tumors such as hepatocellular carcinoma (HCC). In the search for ways to enhance its therapeutic efficacy against solid tumors, we have examined its use in combination with a novel derivative of β-elemene, N-(β-elemene-13-yl)tryptophan methyl ester (ETME). Here we report the effects of the combination on cell viability, apoptosis, the cell cycle and mitochondria membrane potential (MMP) in HCC SMMC-7721 cells. We found that the two compounds acted synergistically to enhance antiproliferative activity and apoptosis. The combination also decreased the MMP, down-regulated Bcl-2 and pro-proteins of the caspase family, and up-regulated Bax and BID, all of which were reversed by the p53 inhibitor, pifithrin-α. In addition, the combination induced cell cycle arrest at the G2/M phase and reduced tumor volume and weight in an xenograft model of nude mice. Overall, the results suggest that ETME in combination with ATO may be useful in the treatment of HCC patients particularly those unresponsive to ATO alone.
authors.affiliation: Food and Drug Vocational College of Guangdong, Guangzhou 510520, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Institute of Chemical Biology, Pharmaceutical College of Henan University, Kaifeng 475004, China.
authors.forename: Fangling
authors.initials: F
authors.lastname: Wu
authors.affiliation: Institute of Chemical Biology, Pharmaceutical College of Henan University, Kaifeng 475004, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
authors.forename: Chaojie
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110015, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Dong
authors.affiliation: Institute of Chemical Biology, Pharmaceutical College of Henan University, Kaifeng 475004, China.
authors.forename: Song-Qiang
authors.initials: SQ
authors.lastname: Xie
keywords: Apoptosis; As2O3; Hepatocarcinoma; p53; β-Elemene derivative