TY - JOUR
T1 - Semisynthetic aurones inhibit tubulin polymerization at the colchicine-binding site and repress PC-3 tumor xenografts in nude mice and myc-induced T-ALL in zebrafish
AU - Xie, Yanqi
AU - Kril, Liliia M.
AU - Yu, Tianxin
AU - Zhang, Wen
AU - Frasinyuk, Mykhaylo S.
AU - Bondarenko, Svitlana P.
AU - Kondratyuk, Kostyantyn M.
AU - Hausman, Elizabeth
AU - Martin, Zachary M.
AU - Wyrebek, Przemyslaw P.
AU - Liu, Xifu
AU - Deaciuc, Agripina
AU - Dwoskin, Linda P.
AU - Chen, Jing
AU - Zhu, Haining
AU - Zhan, Chang Guo
AU - Sviripa, Vitaliy M.
AU - Blackburn, Jessica
AU - Watt, David S.
AU - Liu, Chunming
N1 - Funding Information:
C.L. and D.S.W. were supported by NIH R01 CA172379. D.S.W. was also supported by the Office of the Dean of the College of Medicine, the Markey Cancer Center, and the Center for Pharmaceutical Research and Innovation (CPRI) in the College of Pharmacy, NIH R21 CA205108 (to J. Mohler), Department of Defense Idea Development Award PC150326P2, and NIH P20 RR020171 from the National Institute of General Medical Sciences (to L. Hersh). The authors also thank the University of Kentucky Proteomics Core mass spectrometric measurements using a LTQ-Orbitrap mass spectrometer that was acquired by NIH grant S10 RR029127 to Professor H. Zhu. This research was also supported by the Flow Cytometry and Cell Sorting Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). We thank Markey Biospecimen Procurement & Translational Pathology Shared Resource Facility (BPTP SRF) for processing, H&E and TUNEL staining of the tumor tissues.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5b) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC50 values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and in vitro inhibition of tubulin polymerization indicated that aurone 5a disrupted tubulin dynamics. Based on molecular docking and confirmed by liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone 5a targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones 5a and 5b strongly inhibited in vitro a panel of human leukemia cancer cell lines and the in vivo myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model.
AB - Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5b) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC50 values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and in vitro inhibition of tubulin polymerization indicated that aurone 5a disrupted tubulin dynamics. Based on molecular docking and confirmed by liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone 5a targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones 5a and 5b strongly inhibited in vitro a panel of human leukemia cancer cell lines and the in vivo myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model.
UR - http://www.scopus.com/inward/record.url?scp=85065328238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065328238&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-42917-0
DO - 10.1038/s41598-019-42917-0
M3 - Article
C2 - 31015569
AN - SCOPUS:85065328238
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 6439
ER -