FLLL32 is a STAT3 inhibitor and also inhibits JAK2 kinase activity. FLLL32 inhibited STAT3 phosphorylation at 5μM, DNA-binding activity at 10μM, and transactivation at 5 or 10μMin vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in pancreatic and breast cancer cell lines. It also inhibited colony formation in soft agar and cell invasion and exhibit synergy with the anticancer drug doxorubicin against breast cancer cells. Administration of 50mg/kg FLLL32, i.p., daily, reduced tumor growth in mouse xenograft MDA-MB-231 breast cancer cells[2].
作用机制
FLLL32 selectively binds to Janus kinase 2 and the STAT3 Src homology-2 domain, which serve crucial roles in STAT3 dimerization and signal transduction.[2]
FLLL32 细胞实验
Cell Line
Concentration
Treated Time
Description
References
PBMCs
5 µM
24 hours
FLLL32 did not affect the viability and function of PBMCs.
Mol Cancer. 2010 Jun 25;9:165.
MDA-MB-453 breast cancer cells
10 µM
2 hours pretreatment, 30 minutes IFNα or IL-6 stimulation
Inhibited IFNα and IL-6 induced STAT3 phosphorylation
Cancer Res. 2010 Mar 15;70(6):2445-54.
HEP3B liver cancer cells
2.5-10 µM
24 hours
Inhibited STAT3 phosphorylation, decreased STAT3 downstream target genes, and increased cleavage of caspase-3 and PARP
Mol Cancer. 2010 Aug 16;9:217.
SNU449 liver cancer cells
2.5-10 µM
24 hours
Inhibited STAT3 phosphorylation, decreased STAT3 downstream target genes, and increased cleavage of caspase-3 and PARP
Mol Cancer. 2010 Aug 16;9:217.
U266 multiple myeloma cells
2.5-10 µM
24 hours
Inhibited STAT3 phosphorylation, decreased STAT3 downstream target genes, and increased cleavage of caspase-3 and PARP
Mol Cancer. 2010 Aug 16;9:217.
U87 glioblastoma cells
2.5-10 µM
24 hours
Inhibited STAT3 phosphorylation, decreased STAT3 downstream target genes, and increased cleavage of caspase-3 and PARP
Mol Cancer. 2010 Aug 16;9:217.
HCT-116 colorectal cancer cells
2.5-10 µM
24 hours
Inhibited STAT3 phosphorylation, decreased STAT3 downstream target genes, and increased cleavage of caspase-3 and PARP
Mol Cancer. 2010 Aug 16;9:217.
SW480 colorectal cancer cells
2.5-10 µM
24 hours
Inhibited STAT3 phosphorylation, decreased STAT3 downstream target genes, and increased cleavage of caspase-3 and PARP
FLLL32 treatment only reduced the viability of SG cells by approximately 20%.
Int J Mol Sci. 2021 Nov 1;22(21):11860.
SCC-9
0, 1, 2, 4, 8, 16 µM
24 hours
FLLL32 significantly inhibited the viability of SCC-9 cells, with approximately 90% reduction in cell viability after 24 h treatment with 16 μM.
Int J Mol Sci. 2021 Nov 1;22(21):11860.
HSC-3
0, 1, 2, 4, 8, 16 µM
24 hours
FLLL32 significantly inhibited the viability of HSC-3 cells, with approximately 90% reduction in cell viability after 24 h treatment with 16 μM.
Int J Mol Sci. 2021 Nov 1;22(21):11860.
CD44+/CD24+ pancreatic cancer cells
5 µM
24 hours
Inhibited STAT3 phosphorylation, reduced cell viability and tumorsphere formation
Int J Oncol. 2016 Dec;49(6):2265-2274.
ALDH+ pancreatic cancer cells
5 µM
24 hours
Inhibited STAT3 phosphorylation, reduced cell viability and tumorsphere formation
Int J Oncol. 2016 Dec;49(6):2265-2274.
MPNST cell lines
200 nM
4 days
FLLL32 decreased cell survival in 5/5 tested cell lines
Oncogene. 2014 Jan 9;33(2):173-80.
Hs294T
1.9-2.8 µM (IC 50)
48 hours
FLLL32 induced apoptosis in Hs294T cells and inhibited STAT3 phosphorylation.
Mol Cancer. 2010 Jun 25;9:165.
A375
1.3 µM (IC 50)
48 hours
FLLL32 induced apoptosis in A375 cells and inhibited STAT3 phosphorylation.
Mol Cancer. 2010 Jun 25;9:165.
Pancreatic stellate cells (PSC)
6 µM
48 hours
FLLL32 treatment of PSC inhibited STAT3 phosphorylation, reduced IL-6 production, and decreased cell viability
Cancer Res. 2013 May 15;73(10):3007-18.
TE13
5 µM
48 hours
Inhibit JAK2/STAT3 signaling pathway and detect IL-6 secretion
Cancer Sci. 2016 Jul;107(7):944-54.
TE1
5 µM
48 hours
Inhibit JAK2/STAT3 signaling pathway and detect IL-6 secretion
Cancer Sci. 2016 Jul;107(7):944-54.
Eca109
5 µM
48 hours
Inhibit JAK2/STAT3 signaling pathway and detect IL-6 secretion
Cancer Sci. 2016 Jul;107(7):944-54.
Peripheral blood mononuclear cells (PBMC)
6 µM
7 days
FLLL32 abrogated PSC supernatant or IL-6/GM-CSF-induced MDSC differentiation, indicating this process is STAT3-dependent
Cancer Res. 2013 May 15;73(10):3007-18.
T84 intestinal epithelial cells
50 µM
72 hours
To evaluate the effect of FLLL32 on inflammation-induced paracellular permeability. FLLL32 pretreatment ameliorated IL-6-induced reduction in TEER at 24, 48, and 72 hours, indicating superior barrier protection compared to curcumin in vitro.
J Inflamm Res. 2017 Jun 14;10:75-81.
MDA-MB-453 breast cancer cells
20 µM
Inhibited IL-6-induced STAT3 phosphorylation
Mol Cancer. 2010 Aug 16;9:217.
Normal human Schwann cells
0.5 µM
Did not affect viability of normal human Schwann cells
FLLL32 inhibited STAT3-Y705 phosphorylation, reduced neurofibroma volume and macrophage numbers, and suppressed cell proliferation.
Oncogene. 2019 Apr;38(15):2876-2884
CD-1 mice
Necrotizing enterocolitis (NEC) model
Oral gavage
25 mg/kg
Once daily for 6 days (P9 to P14)
To assess the protective effects of FLLL32 on intestinal inflammation and injury in the NEC model. FLLL32 pretreatment reduced intestinal injury scores, NEC incidence, improved intestinal permeability, and decreased proinflammatory cytokines (TNF-α, IL-6, IL-1β, and GRO-α) levels.
J Inflamm Res. 2017 Jun 14;10:75-81.
NOD/SCID mice
MDA-MB-231 breast cancer xenografts
Intraperitoneal
50 mg/kg
Daily for 18 days
Suppressed tumor growth
Mol Cancer. 2010 Aug 16;9:217.
Nude mice
MDA-MB-231 breast cancer xenograft model
Intraperitoneal injection
50 mg/kg
Once daily for 19 days
Inhibited tumor growth, reduced tumor volume
Cancer Res. 2010 Mar 15;70(6):2445-54.
MRL/lpr mice
Diffuse proliferative lupus nephritis (DPLN) model
Intraperitoneal injection
50 mg/kg
Once daily for 4 weeks
FLLL32 combined with methylprednisolone therapy significantly inhibited STAT3 activation, improved acute kidney damage, reduced interstitial infiltration of inflammatory cells, and decreased AKI incidence in MRL/lpr mice.
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