TY - JOUR
TI - Targeting colon cancer with the novel STAT3 inhibitor bruceantinol
AU - Wei, Ning
AU - Li, Jun
AU - Fang, Cheng
AU - Chang, Jin
AU - Xirou, Vasiliki
AU - and Syrigos, Nick K.
AU - Marks, Benjamin J.
AU - Chu, Edward
AU - Schmitz,
AU - John C.
JO - Oncogenesis
PY - 2019
VL - 38
TODO - 10
SP - 1676-1687
PB - Nature Publishing Group
SN - 2157-9024
TODO - 10.1038/s41388-018-0547-y
TODO - null
TODO - STAT3, a transcriptional mediator of oncogenic signaling, is
constitutively active in similar to 70% of human cancers. The
development of STAT3 inhibitors remains an active area of research as no
inhibitors have yet to be approved for the treatment of human cancer.
Herein, we revealed that bruceantinol (BOL) is a novel STAT3 inhibitor
demonstrating potent antitumor activity in in vitro and in vivo human
colorectal cancer (CRC) models. BOL strongly inhibited STAT3 DNA-binding
ability (IC50 = 2.4 pM), blocked the constitutive and IL-6-induced STAT3
activation in a dose- and time-dependent manner, and suppressed
transcription of STAT3 target genes encoding anti-apoptosis factors
(MCL-1, PTTG1, and survivin) and cell-cycle regulators (c-Myc).
Structure-activity relationship studies demonstrated that the C15 side
chain on BOL affected its ability to bind STAT3. Administration of 4
mg/kg BOL significantly inhibited CRC tumor xenografts [p < 0.001],
but no effect was observed in a STAT3(-/-) tumor model. Additional
studies showed that BOL effectively sensitized MEK inhibitors through
repression of p-STAT3 and MCL-1 induction, known resistance mechanisms
of MEK inhibition. Taken together, our findings suggest BOL is a novel
therapeutic STAT3 inhibitor that can be used either alone or in
combination with MEK inhibitors for the treatment of human CRC.
ER -