TY - JOUR
T1 - Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma
AU - Bharadwaj, Uddalak
AU - Kris Eckols, T.
AU - Xu, Xuejun
AU - Kasembeli, Moses M.
AU - Chen, Yunyun
AU - Adachi, Makoto
AU - Song, Yongcheng
AU - Mo, Qianxing
AU - Lai, Stephen Y.
AU - Tweardy, David J.
N1 - Funding Information:
This work was supported, in part, by a National Institutes of Health grants CA149783 to DJT, P30 CA125123 to the BCM Cancer Center, AI036211, CA125123, and RR024574 to BCM Cytometry and Cell Sorting Core, BCM, SPORE program 5 P50CA97007 10 awarded to MD Anderson Cancer Center, CA16672 awarded to CCLC at MDA and research grants from the John S. Dunn Gulf Coast Consortium for Chemical Genomics Screening Grant Program to DJT.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - While STAT3 has been validated as a target for treatment of many cancers, including head and neck squamous cell carcinoma (HNSCC), a STAT3 inhibitor is yet to enter the clinic. We used the scaffold of C188, a small-molecule STAT3 inhibitor previously identified by us, in a hit-to-lead program to identify C188-9. C188-9 binds to STAT3 with high affinity and represents a substantial improvement over C188 in its ability to inhibit STAT3 binding to its pY-peptide ligand, to inhibit cytokine-stimulated pSTAT3, to reduce constitutive pSTAT3 activity in multiple HNSCC cell lines, and to inhibit anchorage dependent and independent growth of these cells. In addition, treatment of nude mice bearing xenografts of UM-SCC-17B, a radioresistant HNSCC line, with C188-9, but not C188, prevented tumor xenograft growth. C188-9 treatment modulated many STAT3-regulated genes involved in oncogenesis and radioresistance, as well as radioresistance genes regulated by STAT1, due to its potent activity against STAT1, in addition to STAT3. C188-9 was well tolerated in mice, showed good oral bioavailability, and was concentrated in tumors. Thus, C188-9, either alone or in combination with radiotherapy, has potential for use in treating HNSCC tumors that demonstrate increased STAT3 and/or STAT1 activation.
AB - While STAT3 has been validated as a target for treatment of many cancers, including head and neck squamous cell carcinoma (HNSCC), a STAT3 inhibitor is yet to enter the clinic. We used the scaffold of C188, a small-molecule STAT3 inhibitor previously identified by us, in a hit-to-lead program to identify C188-9. C188-9 binds to STAT3 with high affinity and represents a substantial improvement over C188 in its ability to inhibit STAT3 binding to its pY-peptide ligand, to inhibit cytokine-stimulated pSTAT3, to reduce constitutive pSTAT3 activity in multiple HNSCC cell lines, and to inhibit anchorage dependent and independent growth of these cells. In addition, treatment of nude mice bearing xenografts of UM-SCC-17B, a radioresistant HNSCC line, with C188-9, but not C188, prevented tumor xenograft growth. C188-9 treatment modulated many STAT3-regulated genes involved in oncogenesis and radioresistance, as well as radioresistance genes regulated by STAT1, due to its potent activity against STAT1, in addition to STAT3. C188-9 was well tolerated in mice, showed good oral bioavailability, and was concentrated in tumors. Thus, C188-9, either alone or in combination with radiotherapy, has potential for use in treating HNSCC tumors that demonstrate increased STAT3 and/or STAT1 activation.
KW - C188-9
KW - Cancer
KW - HNSCC
KW - STAT3
KW - Small molecule
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U2 - 10.18632/oncotarget.8368
DO - 10.18632/oncotarget.8368
M3 - Article
C2 - 27027445
AN - SCOPUS:84967154648
SN - 1949-2553
VL - 7
SP - 26307
EP - 26330
JO - Oncotarget
JF - Oncotarget
IS - 18
ER -