TY - JOUR
T1 - Oral proteasomal inhibitors ixazomib, oprozomib, and delanzomib upregulate the function of organic anion transporter 3 (OAT3)
T2 - Implications in OAT3-mediated drug-drug interactions
AU - Fan, Yunzhou
AU - Liang, Zhengxuan
AU - Zhang, Jinghui
AU - You, Guofeng
N1 - Funding Information:
Funding: This research was funded by grants (to Guofeng You) from National Institute of General Medical Sciences (R01-GM079123 and R01-GM127788).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/3
Y1 - 2021/3
N2 - Organic anion transporter 3 (OAT3) is mainly expressed at the basolateral membrane of kidney proximal tubules, and is involved in the renal elimination of various kinds of important drugs, potentially affecting drug efficacy or toxicity. Our laboratory previously reported that ubiquitin modification of OAT3 triggers the endocytosis of OAT3 from the plasma membrane to intracellular endosomes, followed by degradation. Oral anticancer drugs ixazomib, oprozomib, and delanzomib, as proteasomal inhibitors, target the ubiquitin–proteasome system in clinics. Therefore, this study investigated the effects of ixazomib, oprozomib, and delanzomib on the expression and transport activity of OAT3 and elucidated the underlying mechanisms. We showed that all three drugs sig-nificantly increased the accumulation of ubiquitinated OAT3, which was consistent with decreased intracellular 20S proteasomal activity; stimulated OAT3-mediated transport of estrone sulfate and p-aminohippuric acid; and increased OAT3 surface expression. The enhanced transport activity and OAT3 expression following drug treatment resulted from an increase in maximum transport velocity of OAT3 without altering the substrate binding affinity, and from a decreased OAT3 degradation. Together, our study discovered a novel role of anticancer agents ixazomib, oprozomib, and delan-zomib in upregulating OAT3 function, unveiled the proteasome as a promising target for OAT3 regulation, and provided implication of OAT3-mediated drug–drug interactions, which should be warned against during combination therapies with proteasome inhibitor drugs.
AB - Organic anion transporter 3 (OAT3) is mainly expressed at the basolateral membrane of kidney proximal tubules, and is involved in the renal elimination of various kinds of important drugs, potentially affecting drug efficacy or toxicity. Our laboratory previously reported that ubiquitin modification of OAT3 triggers the endocytosis of OAT3 from the plasma membrane to intracellular endosomes, followed by degradation. Oral anticancer drugs ixazomib, oprozomib, and delanzomib, as proteasomal inhibitors, target the ubiquitin–proteasome system in clinics. Therefore, this study investigated the effects of ixazomib, oprozomib, and delanzomib on the expression and transport activity of OAT3 and elucidated the underlying mechanisms. We showed that all three drugs sig-nificantly increased the accumulation of ubiquitinated OAT3, which was consistent with decreased intracellular 20S proteasomal activity; stimulated OAT3-mediated transport of estrone sulfate and p-aminohippuric acid; and increased OAT3 surface expression. The enhanced transport activity and OAT3 expression following drug treatment resulted from an increase in maximum transport velocity of OAT3 without altering the substrate binding affinity, and from a decreased OAT3 degradation. Together, our study discovered a novel role of anticancer agents ixazomib, oprozomib, and delan-zomib in upregulating OAT3 function, unveiled the proteasome as a promising target for OAT3 regulation, and provided implication of OAT3-mediated drug–drug interactions, which should be warned against during combination therapies with proteasome inhibitor drugs.
KW - Drug transporter
KW - Ixazomib
KW - Regulation
KW - Ubiquitination
UR - http://www.scopus.com/inward/record.url?scp=85102281855&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102281855&partnerID=8YFLogxK
U2 - 10.3390/pharmaceutics13030314
DO - 10.3390/pharmaceutics13030314
M3 - Article
AN - SCOPUS:85102281855
SN - 1999-4923
VL - 13
SP - 1
EP - 16
JO - Pharmaceutics
JF - Pharmaceutics
IS - 3
M1 - 314
ER -