The Multidrug Resistance Transporter P-glycoprotein Confers Resistance to Ferroptosis Inducers

by Selleckchem | Apr 26 2023

Ferroptosis is a form of cell death caused by direct or indirect inhibition of glutathione peroxidase 4 that leads to lethal lipid peroxidation. Several small molecule ferroptosis inducers (FINs) have been reported, yet little information is available regarding resistance mechanisms, particularly their interaction with the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp, ABCB1) and ABCG2. Given the role that ABC transporters play in absorption, distribution, and excretion of many drugs, characterizing these interactions could provide information regarding oral bioavailability and brain penetration and may predict drug-drug interactions. Using ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2, we found that P-gp overexpression was able to confer resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin. Results were confirmed with OVCAR8-derived NCI/ADR-RES cells that overexpress P-gp, where the P-gp inhibitor valspodar completely inhibited resistance to the FINs. P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of ABCB1 . At a concentration of 10 μM, the FINs ML-162, GPX inhibitor 26a, and PACMA31 were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 cells and GPX inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 cells. Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain. The ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.

Significance statement: While several small-molecule ferroptosis inducers have been described, little work has addressed potential interactions with ABC transporters such as P-glycoprotein or ABCG2 that might limit bioavailability or brain penetration. We find that the ferroptosis inducers FIN56, imidazole ketone erastin, and piperazine erastin are substrates of P-glycoprotein. ML-162, GPX inhibitor 26a, and PACMA31 were found to inhibit P-glycoprotein, while GPX inhibitor 26a was additionally able to inhibit ABCG2, suggesting the potential for drug-drug interactions.

Comments：

The passage describes the results of a study that investigated the interaction of small molecule ferroptosis inducers (FINs) with the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp, ABCB1) and ABCG2. The study found that overexpression of P-gp can confer resistance to FIN56, imidazole ketone erastin, and piperazine erastin in ferroptosis-sensitive cells. This resistance was confirmed in another set of cells that overexpress P-gp, and it was reversed by the P-gp inhibitor valspodar. The study also found that some FINs, including ML-162, GPX inhibitor 26a, and PACMA31, were able to increase intracellular fluorescence in P-gp-expressing cells, indicating that they are substrates of P-gp. Moreover, GPX inhibitor 26a was able to inhibit ABCG2, suggesting the potential for drug-drug interactions.

The significance statement highlights that while several small-molecule ferroptosis inducers have been described, little work has addressed potential interactions with ABC transporters such as P-glycoprotein or ABCG2 that might limit bioavailability or brain penetration. The study's findings suggest that expression of P-gp may reduce the efficacy of some FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain. Additionally, the ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.