Date of Award

2026

Document Type

Dissertation

Degree Name

Pharmaceutical Sciences (Ph.D.)

Department

Pharmaceutical Sciences

First Advisor

John N.D. Wurpel

Second Advisor

Sandra E. Reznik

Third Advisor

Zhe-Sheng Chen

Abstract

Overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, is a major mechanism of multidrug resistance (MDR) and contributes to chemotherapy failure by reducing intracellular drug accumulation. Umbralisib is a dual inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε) that was developed for the treatment of hematologic malignancies; however, it was later withdrawn due to safety concerns. In the present study, we found that umbralisib has the potential to reverse ABCB1-mediated MDR. The MTT assay demonstrated that umbralisib significantly sensitized ABCB1-overexpressing KB-C2 and SW620/Ad300 cells, as well as ABCB1-transfected HEK293 cells. Mechanistic assays revealed that umbralisib enhanced intracellular [3H]-paclitaxel accumulation and reduced [3H]-paclitaxel efflux in ABCB1-overexpressing cells, indicating inhibition of ABCB1-mediated drug efflux. ATPase analysis further showed that umbralisib stimulated ABCB1 ATPase activity in a concentration-dependent manner, supporting direct interaction with the transporter. Molecular docking analysis showed a favorable binding affinity score of -9.64 kcal/mol for umbralisib with the ABCB1 model, supporting its interaction within the transmembrane drug-binding cavity. Furthermore, umbralisib did not significantly alter ABCB1 protein expression or membrane localization. Consistently, umbralisib also increased apoptosis of substrate drug and sustained reversal activity in a 3D tumor spheroid model. Notably, the reversal effect was observed at concentrations at 10 μM, which appears pharmacologically relevant in relation to clinically reported exposure ranges for umbralisib. In summary, our study uncovers a novel potential for repurposing umbralisib as a functional inhibitor of ABCB1-mediated MDR.

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