Polyphenols from Korean prostrate spurge Euphorbia supina induce apoptosis through the Fas-associated extrinsic pathway and activation of ERK in human leukemic U937 cells.

Abstract

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.

• Authors: Min-Ho Han, Won Sup Lee, Arulkumar Nagappan, Hye Jung Kim, Cheol Park, Gi-Young Kim, Sang Hoon Hong, Nam Deuk Kim, Gonsup Kim, Chung Ho Ryu, Sung Chul Shin, Yung Hyun Choi
• Journal: Oncology reports (Oncol Rep) Vol. 36 Issue 1 Pg. 99-107 (Jul 2016) ISSN: 1791-2431 [Electronic] Greece
• PMID: 27122127 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BAD protein, human
• BH3 Interacting Domain Death Agonist Protein
• BID protein, human
• Inhibitor of Apoptosis Proteins
• Phosphoinositide-3 Kinase Inhibitors
• Phytochemicals
• Polyphenols
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• bcl-2-Associated X Protein
• bcl-Associated Death Protein
• Cytochromes c
• BIRC3 protein, human
• Baculoviral IAP Repeat-Containing 3 Protein
• Ubiquitin-Protein Ligases
• Poly(ADP-ribose) Polymerases
• Extracellular Signal-Regulated MAP Kinases
• Caspase 3
• Caspase 8
• Caspase 9

Topics

• Antineoplastic Agents (isolation & purification, pharmacology)
• Apoptosis (drug effects)
• BH3 Interacting Domain Death Agonist Protein (metabolism)
• Baculoviral IAP Repeat-Containing 3 Protein
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytochromes c (metabolism)
• DNA Fragmentation (drug effects)
• Enzyme Activation (drug effects)
• Euphorbia (chemistry)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Leukemia (drug therapy, pathology)
• MAP Kinase Signaling System (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Phosphoinositide-3 Kinase Inhibitors
• Phytochemicals (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Polyphenols (isolation & purification, pharmacology)
• Republic of Korea
• U937 Cells
• Ubiquitin-Protein Ligases (metabolism)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)
• bcl-2-Associated X Protein (biosynthesis)
• bcl-Associated Death Protein (biosynthesis)