PMID- 26508031
OWN - NLM
STAT- MEDLINE
DCOM- 20170202
LR  - 20220316
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 37
IP  - 4
DP  - 2016 Apr
TI  - Esculetin, a natural coumarin compound, evokes Ca(2+) movement and activation of 
      Ca(2+)-associated mitochondrial apoptotic pathways that involved cell cycle 
      arrest in ZR-75-1 human breast cancer cells.
PG  - 4665-78
LID - 10.1007/s13277-015-4286-1 [doi]
AB  - Esculetin (6,7-dihydroxycoumarin), a derivative of coumarin compound, is found in 
      traditional medicinal herbs. It has been shown that esculetin triggers diverse 
      cellular signal transduction pathways leading to regulation of physiology in 
      different models. However, whether esculetin affects Ca(2+) homeostasis in breast 
      cancer cells has not been explored. This study examined the underlying mechanism 
      of cytotoxicity induced by esculetin and established the relationship between 
      Ca(2+) signaling and cytotoxicity in human breast cancer cells. The results 
      showed that esculetin induced concentration-dependent rises in the intracellular 
      Ca(2+) concentration ([Ca(2+)]i) in ZR-75-1 (but not in MCF-7 and MDA-MB-231) 
      human breast cancer cells. In ZR-75-1 cells, this Ca(2+) signal response was 
      reduced by removing extracellular Ca(2+) and was inhibited by the store-operated 
      Ca(2+) channel blocker 2-aminoethoxydiphenyl borate (2-APB). In Ca(2+)-free 
      medium, pre-treatment with the endoplasmic reticulum Ca(2+) pump inhibitor 
      thapsigargin (TG) abolished esculetin-induced [Ca(2+)]i rises. Conversely, 
      incubation with esculetin abolished TG-induced [Ca(2+)]i rises. Esculetin induced 
      cytotoxicity that involved apoptosis, as supported by the reduction of 
      mitochondrial membrane potential and the release of cytochrome c and the 
      proteolytic activation of caspase-9/caspase-3, which were partially reversed by 
      pre-chelating cytosolic Ca(2+) with 
      1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester 
      (BAPTA-AM). Moreover, esculetin increased the percentage of cells in G2/M phase 
      and regulated the expressions of p53, p21, CDK1, and cyclin B1. Together, in 
      ZR-75-1 cells, esculetin induced [Ca(2+)]i rises by releasing Ca(2+) from the ER 
      and causing Ca(2+) influx through 2-APB-sensitive store-operated Ca(2+) entry. 
      Furthermore, esculetin activated Ca(2+)-associated mitochondrial apoptotic 
      pathways that involved G2/M cell cycle arrest. Graphical abstract The summary of 
      esculetin-evoked [Ca(2+)]i rises and -activated Ca(2+)-associated mitochondrial 
      apoptotic pathways that involved cell cycle arrest. The natural coumarin 
      derivative esculetin caused Ca(2+) influx via 2-APB-sensitive store-operated 
      Ca(2+) entry and induced Ca(2+) release from the endoplasmic reticulum. Moreover, 
      esculetin activated the mitochondrial pathway of apoptosis in a Ca(2+)-associated 
      manner that involved G2/M arrest.
FAU - Chang, Hong-Tai
AU  - Chang HT
AD  - Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, 813, 
      Taiwan, Republic of China.
FAU - Chou, Chiang-Ting
AU  - Chou CT
AD  - Department of Nursing, Division of Basic Medical Sciences, Chang Gung University 
      of Science and Technology, Chia-Yi, 613, Taiwan.
AD  - Chronic Diseases and Health Promotion Research Center, Chang Gung University of 
      Science and Technology, Chia-Yi, 613, Taiwan.
FAU - Lin, You-Sheng
AU  - Lin YS
AD  - Department of Medical Education and Research, Kaohsiung Veterans General 
      Hospital, Kaohsiung, 813, Taiwan.
FAU - Shieh, Pochuen
AU  - Shieh P
AD  - Department of Pharmacy, Tajen University, Pingtung, 907, Taiwan.
FAU - Kuo, Daih-Huang
AU  - Kuo DH
AD  - Department of Pharmacy, Tajen University, Pingtung, 907, Taiwan.
FAU - Jan, Chung-Ren
AU  - Jan CR
AD  - Department of Medical Education and Research, Kaohsiung Veterans General 
      Hospital, Kaohsiung, 813, Taiwan.
FAU - Liang, Wei-Zhe
AU  - Liang WZ
AD  - Department of Medical Education and Research, Kaohsiung Veterans General 
      Hospital, Kaohsiung, 813, Taiwan. lianggoole67@gmail.com.
LA  - eng
PT  - Journal Article
DEP - 20151028
PL  - Netherlands
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental 
      Biology and Medicine
JID - 8409922
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Umbelliferones)
RN  - SM2XD6V944 (esculetin)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Antineoplastic Agents, Phytogenic/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Breast Neoplasms/drug therapy
MH  - Calcium
MH  - Calcium Signaling
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Line, Tumor
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - G1 Phase Cell Cycle Checkpoints
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mitochondria
MH  - Umbelliferones/*pharmacology
OTO - NOTNLM
OT  - Ca2+
OT  - Cell cycle
OT  - Esculetin
OT  - Human breast cancer cells
OT  - Mitochondrial apoptotic pathway
EDAT- 2015/10/29 06:00
MHDA- 2017/02/06 06:00
CRDT- 2015/10/29 06:00
PHST- 2015/09/16 00:00 [received]
PHST- 2015/10/19 00:00 [accepted]
PHST- 2015/10/29 06:00 [entrez]
PHST- 2015/10/29 06:00 [pubmed]
PHST- 2017/02/06 06:00 [medline]
AID - 10.1007/s13277-015-4286-1 [pii]
AID - 10.1007/s13277-015-4286-1 [doi]
PST - ppublish
SO  - Tumour Biol. 2016 Apr;37(4):4665-78. doi: 10.1007/s13277-015-4286-1. Epub 2015 
      Oct 28.