Induction of apoptosis by esculetin in human leukemia U937 cells: roles of Bcl-2 and extracellular-regulated kinase signaling.
In the present study, we reported that apoptosis induced by esculetin, a phenolic compound with apoptotic activity in cancer cells, was markedly blocked by Bcl-2-overexpression, but restored by HA14-1, a small-molecule Bcl-2 inhibitor, in human leukemic U937 cells. The combined use of esculetin and HA14-1 effectively induced Bid cleavage and loss of mitochondrial membrane potential (MMP, Deltapsi(m)) leading to the activation of caspases and cleavage of poly(ADP-ribose) polymerase (PARP) in Bcl-2-overexpressing (U937/Bcl-2) cells. Combined treatment with esculetin and HA14-1 upregulated the expression of death receptor 4 (DR4), and activation of extracellular-regulated kinase (ERK) in a time-dependent manner. In addition, esculetin and HA14-1-mediated apoptosis was reduced by ERK inhibitors through inhibition of DR4 expression, suggesting that the synergistic effect was at least partially mediated through ERK-dependent induction of DR4 expression. The results indicate that HA14-1-induced reversal of the anti-apoptotic effect of Bcl-2 confers apoptosis sensitivity to esculetin by a mitochondrial amplification step and through the ERK-dependent induction of DR4 expression in U937/Bcl-2 cells. Thus, HA14-1 reversal of Bcl-2-mediated esculetin resistance suggests a novel strategy for increasing esculetin sensitivity in Bcl-2-overexpressing leukemia cells.
Park
Cheol
C
Blue-Bio Industry Regional Innovation Center, Dongeui University, Busan 614-714, Republic of Korea.
Jin
Cheng-Yun
CY
Kwon
Hyun Ju
HJ
Hwang
Hye Jin
HJ
Kim
Gi-Young
GY
Choi
Il Whan
IW
Kwon
Taeg Kyu
TK
Kim
Byung-Woo
BW
Kim
Wun-Jae
WJ
Choi
Yung Hyun
YH
D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D020298:U937 Cells; D014468:Umbelliferones / Q000633:toxicity*
D001578:Benzopyrans; D004791:Enzyme Inhibitors; D009570:Nitriles; D014468:Umbelliferones; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D048049:Extracellular Signal-Regulated MAP Kinases; C007628:esculetin