title: Icariside II induces apoptosis in U937 acute myeloid leukemia cells: role of inactivation of STAT3-related signaling.
abstract: BACKGROUND
  The aim of this study is to determine anti-cancer effect of Icariside II purified from the root of Epimedium koreanum Nakai on human acute myeloid leukemia (AML) cell line U937.
  
  
  RESULTS
  Icariside II blocked the growth U937 cells in a dose- and time-dependent manner. In this anti-proliferation process, this herb compound rendered the cells susceptible to apoptosis, manifested by enhanced accumulation of sub-G1 cell population and increased the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Icariside II was able to activate caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) in a time-dependent manner. Concurrently, the anti-apoptotic proteins, such as bcl-x(L) and survivin in U937 cells, were downregulated by Icariside II. In addition, Icariside II could inhibit STAT3 phosphorylation and function and subsequently suppress the activation of Janus activated kinase 2 (JAK2), the upstream activators of STAT3, in a dose- and time-dependent manner. Icariside II also enhanced the expression of protein tyrosine phosphatase (PTP) SH2 domain-containing phosphatase (SHP)-1, and the addition of sodium pervanadate (a PTP inhibitor) prevented Icariside II-induced apoptosis as well as STAT3 inactivation in STAT3 positive U937 cells. Furthermore, silencing SHP-1 using its specific siRNA significantly blocked STAT3 inactivation and apoptosis induced by Icariside II in U937 cells.
  
  
  CONCLUSIONS
  Our results demonstrated that via targeting STAT3-related signaling, Icariside II sensitizes U937 cells to apoptosis and perhaps serves as a potent chemotherapeutic agent for AML.
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Kang
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.forename: Wonil
authors.initials: W
authors.lastname: Koh
authors.forename: Jung Hyo
authors.initials: JH
authors.lastname: Kim
authors.forename: Dae Keun
authors.initials: DK
authors.lastname: Kim
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Chen
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D034181:Epimedium / Q000737:chemistry*; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D010936:Plant Extracts / Q000737:chemistry; D018517:Plant Roots / Q000737:chemistry*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077022:Survivin; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; D005419:Flavonoids; D051034:Inhibitor of Apoptosis Proteins; D010936:Plant Extracts; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D051020:bcl-X Protein; C060988:baohuoside I; D011065:Poly(ADP-ribose) Polymerases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D053148:Caspase 3