PMID- 19428345
OWN - NLM
STAT- MEDLINE
DCOM- 20090602
LR  - 20181201
IS  - 1872-7786 (Electronic)
IS  - 0009-2797 (Linking)
VI  - 180
IP  - 1
DP  - 2009 Jun 15
TI  - Enhancement of esculetin on arsenic trioxide-provoked apoptosis in human leukemia 
      U937 cells.
PG  - 61-8
LID - 10.1016/j.cbi.2009.01.011 [doi]
AB  - In order to overcome chemotherapy resistance, many laboratories are searching for 
      agents that increase the sensitivity of cancer cells to anticancer drugs. Arsenic 
      trioxide (As(2)O(3)) is widely used in treating human acute polymyelocytic 
      leukemia (APL). However, solid tumors and other leukemia cells such as U937 
      promonocytic leukemia cells are insensitive to As(2)O(3). Esculetin, a coumarin 
      derivative, has previously induced cell cycle arrest and apoptosis of HL-60 cells 
      as well as enhanced taxol-induced apoptosis in HepG2 cells, thereby displaying 
      anticancer potential. In this study, esculetin inhibited proliferation and 
      mitogen activated protein kinases (MAPKs) activation in human leukemia U937 
      cells. Since inhibitors of MAPKs have modulated the GSH-redox state and enhanced 
      the sensitivity of leukemia cells to As(2)O(3)-provoked apoptosis, we monitored 
      the effect of combining esculetin and As(2)O(3) (2.5 microM) on the GSH level. 
      Our study showed that esculetin, PD98059 (MEK/ERK inhibitor), and SP600125 (JNK 
      inhibitor) similarly enhanced the As(2)O(3)-induced GSH depletion. We found that 
      the As(2)O(3) (2.5 microM) treatment slightly induced apoptosis and the 
      pretreatment of esculetin enhanced the As(2)O(3)-provoked apoptosis 
      significantly. In addition, esculetin enhanced the effect of As(2)O(3) on caspase 
      activation in U937 cells. We compared the combined esculetin and As(2)O(3) 
      treatment to the As(2)O(3) treated alone. The combined esculetin and As(2)O(3) 
      treatment increased Bid cleavage, Bax conformation change and cytochrome C 
      release. The study also indicated that esculetin enhanced the As(2)O(3)-induced 
      lysosomal leakage and apoptosis. Furthermore, pretreatment with N-acetylcysteine 
      (NAC) reduced these enhanced effects. Based on these studies, esculetin enhances 
      the As(2)O(3)-provoked apoptosis by modulating the MEK/ERK and JNK pathways and 
      reducing intracellular GSH levels. GSH depletion led to higher oxidative stress 
      which activated lysosomal-mitochondrial pathway of apoptosis.
FAU - Lin, Tseng-Hsi
AU  - Lin TH
AD  - Institute of Biochemistry and Biotechnology, Chung Shan Medical University, 
      Taichung, Taiwan.
FAU - Lu, Fung-Jou
AU  - Lu FJ
FAU - Yin, Yu-Fang
AU  - Yin YF
FAU - Tseng, Tsui-Hwa
AU  - Tseng TH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090129
PL  - Ireland
TA  - Chem Biol Interact
JT  - Chemico-biological interactions
JID - 0227276
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antioxidants)
RN  - 0 (Arsenicals)
RN  - 0 (Oxides)
RN  - 0 (Umbelliferones)
RN  - S7V92P67HO (Arsenic Trioxide)
RN  - SM2XD6V944 (esculetin)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Antioxidants/therapeutic use
MH  - Apoptosis/*drug effects
MH  - Arsenic Trioxide
MH  - Arsenicals/*pharmacology
MH  - Blotting, Western
MH  - Cell Survival
MH  - Fluorescent Antibody Technique
MH  - Humans
MH  - *Leukemia
MH  - Oxides/*pharmacology
MH  - U937 Cells
MH  - Umbelliferones/*pharmacology
EDAT- 2009/05/12 09:00
MHDA- 2009/06/03 09:00
CRDT- 2009/05/12 09:00
PHST- 2008/11/05 00:00 [received]
PHST- 2009/01/20 00:00 [revised]
PHST- 2009/01/20 00:00 [accepted]
PHST- 2009/05/12 09:00 [entrez]
PHST- 2009/05/12 09:00 [pubmed]
PHST- 2009/06/03 09:00 [medline]
AID - S0009-2797(09)00035-0 [pii]
AID - 10.1016/j.cbi.2009.01.011 [doi]
PST - ppublish
SO  - Chem Biol Interact. 2009 Jun 15;180(1):61-8. doi: 10.1016/j.cbi.2009.01.011. Epub 
      2009 Jan 29.