Developing antineoplastic agents that target peroxisomal enzymes: Cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)

Mykhaylo S. Frasinyuk; Wen Zhang; Przemyslaw Wyrebek; Tianxin Yu; Xuehe Xu; Vitaliy M. Sviripa; Svitlana P. Bondarenko; Yanqi Xie; Huy X. Ngo; Andrew J. Morris; James L. Mohler; Michael V. Fiandalo; David S. Watt; Chunming Liu

doi:10.1039/c7ob01584d

Developing antineoplastic agents that target peroxisomal enzymes: Cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)

Mykhaylo S. Frasinyuk, Wen Zhang, Przemyslaw Wyrebek, Tianxin Yu, Xuehe Xu, Vitaliy M. Sviripa, Svitlana P. Bondarenko, Yanqi Xie, Huy X. Ngo, Andrew J. Morris, James L. Mohler, Michael V. Fiandalo, David S. Watt, Chunming Liu

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.

Original language	English
Pages (from-to)	7623-7629
Number of pages	7
Journal	Organic and Biomolecular Chemistry
Volume	15
Issue number	36
DOIs	https://doi.org/10.1039/c7ob01584d
State	Published - 2017

Bibliographical note

Publisher Copyright:
© 2017 The Royal Society of Chemistry.

Funding

CL and DSW were supported by NIH R01 CA172379. DSW was also supported by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, and NIH R21 CA205108 (to J. Mohler), the Department of Defense Idea Development Award W81XWH-16-1-0635, NIH P20 RR020171 from the National Institute of General Medical Sciences (to L. Hersh), and NIH UL1 TR000117 from the National Institutes of Health for the University of Kentucky’s Center for Clinical and Translational Science.

Funders	Funder number
Center for Pharmaceutical Research and Innovation	R21 CA205108
National Institutes of Health for University of Kentucky’s Center for Clinical and Translational Science
National Institutes of Health (NIH)	R01 CA172379
U.S. Department of Defense	W81XWH-16-1-0635, P20 RR020171
National Childhood Cancer Registry – National Cancer Institute	R21CA205108
National Institute of General Medical Sciences	UL1 TR000117

ASJC Scopus subject areas

Biochemistry
Physical and Theoretical Chemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1039/c7ob01584d

Cite this

Frasinyuk, M. S., Zhang, W., Wyrebek, P., Yu, T., Xu, X., Sviripa, V. M., Bondarenko, S. P., Xie, Y., Ngo, H. X., Morris, A. J., Mohler, J. L., Fiandalo, M. V., Watt, D. S., & Liu, C. (2017). Developing antineoplastic agents that target peroxisomal enzymes: Cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4). Organic and Biomolecular Chemistry, 15(36), 7623-7629. https://doi.org/10.1039/c7ob01584d

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title = "Developing antineoplastic agents that target peroxisomal enzymes: Cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)",

abstract = "Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.",

author = "Frasinyuk, {Mykhaylo S.} and Wen Zhang and Przemyslaw Wyrebek and Tianxin Yu and Xuehe Xu and Sviripa, {Vitaliy M.} and Bondarenko, {Svitlana P.} and Yanqi Xie and Ngo, {Huy X.} and Morris, {Andrew J.} and Mohler, {James L.} and Fiandalo, {Michael V.} and Watt, {David S.} and Chunming Liu",

note = "Publisher Copyright: {\textcopyright} 2017 The Royal Society of Chemistry.",

year = "2017",

doi = "10.1039/c7ob01584d",

language = "English",

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pages = "7623--7629",

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Frasinyuk, MS, Zhang, W, Wyrebek, P, Yu, T, Xu, X, Sviripa, VM, Bondarenko, SP, Xie, Y, Ngo, HX, Morris, AJ, Mohler, JL, Fiandalo, MV, Watt, DS & Liu, C 2017, 'Developing antineoplastic agents that target peroxisomal enzymes: Cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)', Organic and Biomolecular Chemistry, vol. 15, no. 36, pp. 7623-7629. https://doi.org/10.1039/c7ob01584d

Developing antineoplastic agents that target peroxisomal enzymes: Cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4). / Frasinyuk, Mykhaylo S.; Zhang, Wen; Wyrebek, Przemyslaw et al.
In: Organic and Biomolecular Chemistry, Vol. 15, No. 36, 2017, p. 7623-7629.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

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AU - Frasinyuk, Mykhaylo S.

AU - Zhang, Wen

AU - Wyrebek, Przemyslaw

AU - Yu, Tianxin

AU - Xu, Xuehe

AU - Sviripa, Vitaliy M.

AU - Bondarenko, Svitlana P.

AU - Xie, Yanqi

AU - Ngo, Huy X.

AU - Morris, Andrew J.

AU - Mohler, James L.

AU - Fiandalo, Michael V.

AU - Watt, David S.

AU - Liu, Chunming

PY - 2017

Y1 - 2017

N2 - Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.

AB - Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.

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AN - SCOPUS:85029761843

SN - 1477-0520

VL - 15

SP - 7623

EP - 7629

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

IS - 36

ER -

Developing antineoplastic agents that target peroxisomal enzymes: Cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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