Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Abstract

Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.

Phase I trial of palbociclib, a selective cyclin dependent kinase 4/6 inhibitor, in combination with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma

“…Alternatively, palbociclib could have exerted its therapeutic activity in these patients via an off-target effect. Despite its specificity for CDK4/6, palbociclib has been reported to have additional and unexpected targets, such as cell membrane transporters[33]. While the clinical relevance of this finding remains to be validated, the possibility that palbociclib can inhibit tumor growth via a non-CDK dependent mechanism (in addition to CDK4 inhibition) is intriguing.…”

Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation

“…Indeed, coadministration of probenecid to inhibit hOAT1-mediated uptake of cidofovir is used clinically to prevent intrarenal accumulation and nephrotoxicity of cidofovir (Cundy et al, 1995;Cihlar et al, 1999). Inhibition of hOCT2-mediated renal cisplatin uptake is also being explored as a strategy to ameliorate cisplatin nephrotoxicity (Filipski et al, 2009;Sprowl et al, 2013;Pabla et al, 2015). On the other hand, inhibition of apical efflux transporters diminishes drug exit from renal cells, which may lead H]cimetidine (10 mM) after application to basal or apical chamber alone or with cold atenolol (1 mM) or metformin (5.5 mM) added in the basal chamber.…”

CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane‐induced alopecia

“…To achieve this, we used the G1 arresting CDK4/6 inhibitor palbociclib, which is used in the treatment of hormone (oestrogen and/or progesterone) receptor‐positive HER2‐negative breast cancer (Ro et al , ). Palbociclib was employed as previous reports have described that pharmacological CDK4/6 inhibition can protect against chemotherapy‐induced acute kidney injury (DiRocco et al , ; Pabla et al , ) and chemotherapy‐induced haematopoietic stem cell exhaustion (He et al , ).…”