title: A derivative of epigallocatechin-3-gallate induces apoptosis via SHP-1-mediated suppression of BCR-ABL and STAT3 signalling in chronic myelogenous leukaemia.
abstract: OBJECTIVE
  Epigallocatechin-3-gallate (EGCG) is a component of green tea known to have chemo-preventative effects on several cancers. However, EGCG has limited clinical application, which necessitates the development of a more effective EGCG prodrug as an anticancer agent.
  
  
  METHODS
  Derivatives of EGCG were evaluated for their stability and anti-tumour activity in human chronic myeloid leukaemia (CML) K562 and KBM5 cells.
  
  
  RESULTS
  EGCG-mono-palmitate (EGCG-MP) showed most prolonged stability compared with other EGCG derivatives. EGCG-MP exerted greater cytotoxicity and apoptosis in K562 and KBM5 cells than the other EGCG derivatives. EGCG-MP induced Src-homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) leading decreased oncogenic protein BCR-ABL and STAT3 phosphorylation in CML cells, compared with treatment with EGCG. Furthermore, EGCG-MP reduced phosphorylation of STAT3 and survival genes in K562 cells, compared with EGCG. Conversely, depletion of SHP-1 or application of the tyrosine phosphatase inhibitor pervanadate blocked the ability of EGCG-MP to suppress phosphorylation of BCR-ABL and STAT3, and the expression of survival genes downstream of STAT3. In addition, EGCG-MP treatment more effectively suppressed tumour growth in BALB/c athymic nude mice compared with untreated controls or EGCG treatment. Immunohistochemistry revealed increased caspase 3 and SHP-1 activity and decreased phosphorylation of BCR-ABL in the EGCG-MP-treated group relative to that in the EGCG-treated group.
  
  
  CONCLUSIONS
  EGCG-MP induced SHP-1-mediated inhibition of BCR-ABL and STAT3 signalling in vitro and in vivo more effectively than EGCG. This derivative may be a potent chemotherapeutic agent for CML treatment.
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Miyong
authors.initials: M
authors.lastname: Yun
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Choo
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Myoung-Seok
authors.initials: MS
authors.lastname: Jeong
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Deok-Beom
authors.initials: DB
authors.lastname: Jung
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Hyemin
authors.initials: H
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Eun-Ok
authors.initials: EO
authors.lastname: Kim
authors.affiliation: The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Bonglee
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Srivastava
authors.affiliation: The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Kaihatsu
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D002392:Catechin; C045651:epigallocatechin gallate; D016044:Fusion Proteins, bcr-abl; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6
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