Polyphenols from Korean prostrate spurge Euphorbia supina induce apoptosis through the Fas-associated extrinsic pathway and activation of ERK in human leukemic U937 cells.
The Korean prostrate spurge Euphorbia supina (Euphorbiaceae family) has been used as a folk medicine in Korea against a variety of ailments such as bronchitis, hemorrhage, jaundice and multiple gastrointestinal diseases. Polyphenols from Korean E. supina (PES) which include quercetin and kaempferol derivatives have anticancer properties. Hence, we investigated the anticancer effects of PES on U937 human leukemic cells. Firstly, PES significantly inhibited the proliferation of U937 cells in a dose-dependent manner. PES induced accumulation of the sub-G1 DNA content (apoptotic cell population), apoptotic bodies and chromatin condensation and DNA fragmentation in the U937 cells. PES also induced activation of caspase-3, -8 and -9, subsequent cleavage of PARP, and significantly suppressed XIAP, cIAP-1 and cIAP-2 in a dose-dependent manner. Furthermore, PES activated Bid, and induced the loss of mitochondrial membrane potential (MMP, ΔΨm) along with upregulation of pro-apoptotic proteins (Bax and Bad), and downregulation of anti-apoptotic proteins (Bcl-2 and Bcl-xL) and cytochrome c release. The Fas receptor was upregulated by PES in a dose-dependent manner, suggesting that the extrinsic pathway was also involved in the PES-induced apoptosis. Moreover, the PES-induced apoptosis was at least in part associated with extracellular signal-regulated kinase (ERK) activation in the U937 human leukemic cells. This study provides evidence that PES may be useful in the treatment of leukemia.
Natural Products Research Team, National Marine Biodiversity Institute of Korea, Seocheon 325-902, Republic of Korea.
Min-Ho
MH
Han
Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
Won Sup
WS
Lee
Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
Arulkumar
A
Nagappan
Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
Hye Jung
HJ
Kim
Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan 614-714, Republic of Korea.
Cheol
C
Park
Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea.
Gi-Young
GY
Kim
Department of Internal Medicine, Dongeui University College of Korean Medicine, Busan 614-052, Republic of Korea.
Sang Hoon
SH
Hong
Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
Nam Deuk
ND
Kim
School of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Republic of Korea.
Gonsup
G
Kim
Division of Applied Life Science (BK 21 Program), Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Republic of Korea.
Chung Ho
CH
Ryu
Department of Chemistry, Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Republic of Korea.
Sung Chul
SC
Shin
Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 614-052, Republic of Korea.
Yung Hyun
YH
Choi
D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D028481:Euphorbia / Q000737:chemistry*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D064209:Phytochemicals / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059808:Polyphenols / Q000302:isolation & purification / Q000494:pharmacology*; D056910:Republic of Korea; D020298:U937 Cells; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051025:bcl-Associated Death Protein / Q000096:biosynthesis
D000970:Antineoplastic Agents; C494819:BAD protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D051034:Inhibitor of Apoptosis Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D064209:Phytochemicals; D059808:Polyphenols; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D045304:Cytochromes c; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9