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

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 ofβ-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.

Design, synthesis and antitumor activity of C3/C3 bis-fluoroquonolones cross-linked with [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazole

To contribute to the development of an efficient method for the conversion of antibacterial fluoroquinolones to antitumor fluoroquinolones,a series of C3/C3 bis-fluoroquinolone fused heterocycles cross-linked with a[1,2,4]-triazolo[3,4-b][1,3,4]-thiadiazole core as a common bioisostere of two carboxylic acid groups was designed and synthesized as their hydrochloride salts.Structures were characterized by elemental analysis and spectral data and their in vitro antitumor activity against L1210,CHO and HL60 cell lines was screened by determination of their IC50 values in the methylthiazole trazolium(MTT)assay.Two compounds were highly potent against the HL60 cell line and represent promising lead compounds for future development.