Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions

Abstract

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 significantly 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 delanzomib 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.

Chloroquine and Hydroxychloroquine, as Proteasome Inhibitors, Upregulate the Expression and Activity of Organic Anion Transporter 3

“…In contrast to direct DDI, in which multiple drugs act directly on the transporter molecule, indirect DDI occurs when one drug acts on the regulatory machinery/pathway of the transporter instead of the transporter itself. This could lead to the alteration of transporter expression and function [ 1 , 48 , 49 ]. As we mentioned before, CQ and HCQ are not OAT3 substrates.…”

“…Numerous widely used drugs, such as antiviral drugs, anticancer therapeutics, antibiotics, antihypertensives, and anti-inflammation drugs, are removed from the body through the organic anion transporter 3 (OAT3) at the basolateral membrane of the kidney proximal tubule cells [ 1 , 2 , 3 ]. OAT3 actively moves drugs from blood into tubule cells.…”

“…OAT3 transport activity vitally relies on its expression level at the plasma membrane, which can be changed under various diseased and pharmacological situations [ 1 , 8 ]. Our laboratory earlier demonstrated that OAT3 constitutively internalizes from and recycles back to the cell surface, and ubiquitin (an 8-kDa polypeptide) conjugation to OAT3 serves as a triggering signal for its internalization to early endosomes [ 9 , 10 ].…”

Delanzomib, a Novel Proteasome Inhibitor, Combined With Adalimumab Drastically Ameliorates Collagen-Induced Arthritis in Rats by Improving and Prolonging the Anti-TNF-α Effect of Adalimumab

“…Although the treatment of delanzomib combined with adalimumab might be potentially beneficial for patients with RA, the safety of this potential therapy needs further evaluation, especially in the case that the dose of delanzomib is increased in the clinical treatment, because delanzomib has been reported to have strong nephrotoxicity similar to bortezomib ( Ruggeri et al, 2009 ; Fan et al, 2021 ). Moreover, further research is also needed to clarify the mechanism by which delanzomib suppressed the degradation of FcRn.…”

Renal Organic Anion Transporters 1 and 3 In Vitro: Gone but Not Forgotten

“…PKC phosphorylates the ubiquitin ligase Nedd4-2 and directly affects the ubiquitination status of OAT1 and OAT3 with a negative impact on the stability and expression of both transporters [71,72]. Evidence from studies involving the selective pharmacological inhibition of proteasomal activity indicates that OAT3 ubiquitination is increased and associated with enhanced membrane expression and anion transport activity [73,74]. Taken together, these findings highlight an important role for both SUMOylation and ubiquitination as the actuators of non-transcriptional regulatory mechanisms of anion transport activity.…”