PMID- 12649187
OWN - NLM
STAT- MEDLINE
DCOM- 20030411
LR  - 20220311
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 63
IP  - 6
DP  - 2003 Mar 15
TI  - Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer 
      and activator of transcription 3 signaling pathway inhibitor with potent 
      antitumor activity against human and murine cancer cells in mice.
PG  - 1270-9
AB  - Constitutively activated, tyrosine-phosphorylated signal transducer and activator 
      of transcription (STAT) 3 plays a pivotal role in human tumor malignancy. To 
      discover disrupters of aberrant STAT3 signaling pathways as novel anticancer 
      drugs, we developed a phosphotyrosine STAT3 cytoblot. Using this high throughput 
      96-well plate assay, we identified JSI-124 (cucurbitacin I) from the National 
      Cancer Institute Diversity Set. JSI-124 suppressed the levels of phosphotyrosine 
      STAT3 in v-Src-transformed NIH 3T3 cells and human cancer cells potently (IC(50) 
      value of 500 nM in the human lung adenocarcinoma A549) and rapidly (complete 
      inhibition within 1-2 h). The suppression of phosphotyrosine STAT3 levels 
      resulted in the inhibition of STAT3 DNA binding and STAT3-mediated but not serum 
      response element-mediated gene transcription. JSI-124 also decreased the levels 
      of tyrosine-phosphorylated Janus kinase (JAK) but not those of Src. JSI-124 was 
      highly selective for JAK/STAT3 and did not inhibit other oncogenic and tumor 
      survival pathways such as those mediated by Akt, extracellular signal-regulated 
      kinase 1/2, or c-Jun NH(2)-terminal kinase. Finally, JSI-124 (1 mg/kg/day) 
      potently inhibited the growth in nude mice of A549 tumors, v-Src-transformed NIH 
      3T3 tumors, and the human breast carcinoma MDA-MB-468, all of which express high 
      levels of constitutively activated STAT3, but it did not affect the growth of 
      oncogenic Ras-transformed NIH 3T3 tumors that are STAT3 independent or of the 
      human lung adenocarcinoma Calu-1, which has barely detectable levels of 
      phosphotyrosine STAT3. JSI-124 also inhibited tumor growth and significantly 
      increased survival of immunologically competent mice bearing murine melanoma with 
      constitutively activated STAT3. These results give strong support for 
      pharmacologically targeting the JAK/STAT3 signaling pathway for anticancer drug 
      discovery.
FAU - Blaskovich, Michelle A
AU  - Blaskovich MA
AD  - Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida 33612, USA.
FAU - Sun, Jiazhi
AU  - Sun J
FAU - Cantor, Alan
AU  - Cantor A
FAU - Turkson, James
AU  - Turkson J
FAU - Jove, Richard
AU  - Jove R
FAU - Sebti, Said M
AU  - Sebti SM
LA  - eng
GR  - CA78038/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Stat3 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Triterpenes)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Jak2 protein, mouse)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - SHQ47990PH (cucurbitacin I)
SB  - IM
MH  - 3T3 Cells
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Division/drug effects
MH  - DNA-Binding Proteins/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Janus Kinase 2
MH  - MAP Kinase Signaling System/drug effects
MH  - Melanoma, Experimental/drug therapy
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Nude
MH  - Phosphorylation
MH  - Phosphotyrosine/metabolism
MH  - *Protein Serine-Threonine Kinases
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - STAT3 Transcription Factor
MH  - Signal Transduction/drug effects
MH  - Trans-Activators/*antagonists & inhibitors/metabolism
MH  - Triterpenes/*pharmacology
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
EDAT- 2003/03/22 04:00
MHDA- 2003/04/12 05:00
CRDT- 2003/03/22 04:00
PHST- 2003/03/22 04:00 [pubmed]
PHST- 2003/04/12 05:00 [medline]
PHST- 2003/03/22 04:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2003 Mar 15;63(6):1270-9.