The aim of the present study is to investigate anticancer effect and mechanism of
regorafenib in
bladder cancer in vitro and in vivo. Human
bladder cancer TSGH 8301 cells were treated with
regorafenib, NF-κB, AKT, or
mitogen-activated protein kinase (MAPK) inhibitors for different time. The changes of cell viability, NF-κB activation, apoptotic signaling transduction, and expression of
tumor progression-associated
proteins were evaluated with MTT, NF-κB reporter gene assay, flow cytometry, and Western blotting assay. TSGH 8301
tumor bearing mice were established and treated with vehicle (140 μL of 0.1%
DMSO) or
regorafenib (10 mg/kg/day by gavage) for 15 days. The changes of
tumor volume,
body weight, NF-κB activation, MAPK activation, and
tumor progression-associated
proteins (
MMP-9, XIAP,
VEGF, and
Cyclin-D1) after
regorafenib treatment were evaluated with digital caliper, digital weight, and ex vivo Western blotting assay. Our results demonstrated NF-κB activation and
protein levels of MMP-9, XIAP,
VEGF, and Cyclin-D1 were significantly reduced by NF-κB (QNZ), ERK (
PD98059), and P38 (
SB203580) inhibitors.
Regorafenib also significantly induced extrinsic and intrinsic apoptotic signaling transduction in
bladder cancer in vitro. In addition,
regorafenib significantly inhibited
tumor growth, NF-κB, p38, ERK activation and expression of
tumor progression-associated
proteins in
bladder cancer in vitro and in vivo. Taken together, these results proved that
regorafenib not only induced apoptosis through extrinsic and intrinsic pathways and but suppressed MAPK/ NF-κB-modulated
tumor progression in
bladder cancer.