PMID- 20215512
OWN - NLM
STAT- MEDLINE
DCOM- 20100426
LR  - 20220316
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 70
IP  - 6
DP  - 2010 Mar 15
TI  - Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity 
      in pancreatic and breast cancer cells.
PG  - 2445-54
LID - 10.1158/0008-5472.CAN-09-2468 [doi]
AB  - The constitutive activation of signal transducer and activator of transcription 3 
      (STAT3) is frequently detected in most types of human cancer where it plays 
      important roles in survival, drug resistance, angiogenesis, and other functions. 
      Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach 
      for these cancers. We have recently developed novel small-molecule STAT3 
      inhibitors, known as FLLL31 and FLLL32, which are derived from curcumin (the 
      primary bioactive compound of turmeric). These compounds are designed to bind 
      selectively to Janus kinase 2 and the STAT3 Src homology-2 domain, which serve 
      crucial roles in STAT3 dimerization and signal transduction. Here we show that 
      FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, DNA-binding 
      activity, and transactivation in vitro, leading to the impediment of multiple 
      oncogenic processes and the induction of apoptosis in pancreatic and breast 
      cancer cell lines. FLLL31 and FLLL32 also inhibit colony formation in soft agar 
      and cell invasion and exhibit synergy with the anticancer drug doxorubicin 
      against breast cancer cells. In addition, we show that FLLL32 can inhibit the 
      induction of STAT3 phosphorylation by IFNalpha and interleukin-6 in breast cancer 
      cells. We also show that administration of FLLL32 can inhibit tumor growth and 
      vascularity in chicken embryo xenografts as well as substantially reduce tumor 
      volumes in mouse xenografts. Our findings highlight the potential of these new 
      compounds and their efficacy in targeting pancreatic and breast cancers that 
      exhibit constitutive STAT3 signaling.
FAU - Lin, Li
AU  - Lin L
AD  - Department of Pediatrics, Division of Medicinal Chemistry and Pharmacognosy, 
      College of Pharmacy, The Ohio State University, Columbus, Ohio 43205, USA. 
      lin.674@osu.edu
FAU - Hutzen, Brian
AU  - Hutzen B
FAU - Zuo, Mingxin
AU  - Zuo M
FAU - Ball, Sarah
AU  - Ball S
FAU - Deangelis, Stephanie
AU  - Deangelis S
FAU - Foust, Elizabeth
AU  - Foust E
FAU - Pandit, Bulbul
AU  - Pandit B
FAU - Ihnat, Michael A
AU  - Ihnat MA
FAU - Shenoy, Satyendra S
AU  - Shenoy SS
FAU - Kulp, Samuel
AU  - Kulp S
FAU - Li, Pui-Kai
AU  - Li PK
FAU - Li, Chenglong
AU  - Li C
FAU - Fuchs, James
AU  - Fuchs J
FAU - Lin, Jiayuh
AU  - Lin J
LA  - eng
GR  - R21 CA133652/CA/NCI NIH HHS/United States
GR  - R21 CA133652-01A1/CA/NCI NIH HHS/United States
GR  - R21CA133652-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100309
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (FLLL 31)
RN  - 0 (FLLL 32)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - IT942ZTH98 (Curcumin)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*drug therapy/metabolism
MH  - Cell Growth Processes
MH  - Cell Line, Tumor
MH  - Chick Embryo
MH  - Curcumin/*analogs & derivatives/pharmacology
MH  - Down-Regulation
MH  - Female
MH  - Humans
MH  - Janus Kinase 2/antagonists & inhibitors
MH  - Mice
MH  - Mice, Nude
MH  - Models, Molecular
MH  - Pancreatic Neoplasms/*drug therapy/metabolism
MH  - Phosphorylation/drug effects
MH  - STAT3 Transcription Factor/*antagonists & inhibitors/metabolism
MH  - Xenograft Model Antitumor Assays
MH  - src Homology Domains
PMC - PMC2843552
MID - NIHMS172762
EDAT- 2010/03/11 06:00
MHDA- 2010/04/27 06:00
PMCR- 2011/03/15
CRDT- 2010/03/11 06:00
PHST- 2010/03/11 06:00 [entrez]
PHST- 2010/03/11 06:00 [pubmed]
PHST- 2010/04/27 06:00 [medline]
PHST- 2011/03/15 00:00 [pmc-release]
AID - 0008-5472.CAN-09-2468 [pii]
AID - 10.1158/0008-5472.CAN-09-2468 [doi]
PST - ppublish
SO  - Cancer Res. 2010 Mar 15;70(6):2445-54. doi: 10.1158/0008-5472.CAN-09-2468. Epub 
      2010 Mar 9.