Downregulation of c-FLIP, XIAP and Mcl-1 protein as well as depletion of reduced glutathione contribute to the apoptosis induction of glycyrrhetinic acid derivatives in leukemia cells

Cancer Biology & Therapy
Dandan SongYongkui Jing

Abstract

The antiproliferative effects and apoptosis inducing abilities of four 18beta-glycyrrhetinic acid (GA) derivatives, methyl 2-cyano-3,11-dioxooleana-1,12-dien-30-oate (CDODO-Me-11), methyl 2-cyano-3,12-dioxooleana-1,12-dien-30-oate (CDODO-Me-12) and their non-esters were investigated in human leukemia cells. Methyl esterification and switching a keto group from position C(11) to C(12) significantly increased the antiproliferative effects. CDODO-Me-11 and CDODO-Me-12 were 10-fold more potent than their non-esters, respectively. CDODO-Me-12 was 10-fold more effective than CDODO-Me-11 in inducing apoptosis which was correlated with the activation of caspase-8 and caspase-9. Western blot analyses revealed that CDODO-Me-12 and CDODO-Me-11 downregulated the levels of anti-apoptosis proteins, c-FLIP, XIAP and Mcl-1, without altering the protein levels of Bcl-2 and the death receptors DR4 and DR5. Both agents decreased the levels of the mitochondrial membrane potential without altering the intracellular H(2)O(2) levels. Jurkat cells without expression of caspase-8 were not sensitive to CDODO-Me-12, but were somewhat responsive to CDODO-Me-11. K562 cells with higher intracellular reduced glutathione (GSH ) levels were less responsive to ...Continue Reading

Citations

Jun 3, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bing XuHai-Min Lei
Jul 27, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yuan GaoLinxiang Zhao
Oct 11, 2012·Natural Product Reports·Jorge A R SalvadorYongkui Jing
Jan 29, 2014·The Journal of Biological Chemistry·Mohankrishna Dalvoy VasudevaraoTapas K Kundu
May 28, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andrey V MarkovMarina A Zenkova
Jan 1, 2014·Journal of Agricultural and Food Chemistry·Tzu-Chien KaoGow-Chin Yen

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