TARGETING CELLULAR METABOLISM BY LEVERAGING THE PHOTOSENSITIZER VERTEPORFIN TO OVERCOME CANCER MULTIDRUG RESISTANCE

Abstract

Overcoming multidrug resistance (MDR) remains one of the major challenges to successful treatment outcomes for cancer patients. P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) drug transporter that effectively translocates substrates (chemotherapeutics in this context) from cancer cells, thus reducing their efficacy over time. Chemoresistance is responsible for approximately 90% of treatment failure in the clinic, demonstrating a need for effective P-gp inhibition strategies to overcome MDR. Traditional approaches for inhibiting ATP-dependent P-gp-mediated drug efflux using as small molecule inhibitors and antibodies have had limited clinical success in part due to low selectivity causing systemic toxicity. Photochemical approaches emerge as an alternative inhibition strategy to overcome P-gp-mediated MDR. Previous research has shown that photoactivation of the photosensitizer, verteporfin (VP), can directly cause P-gp aggregation due to cross-linking of the protein. Photoactivation of VP resulting in indirect P-gp inhibition, such as by depleting ATP levels, has been understudied. In this context, this thesis aims to understand the mechanisms through which ATP-depletion is an indirect target for P-gp inhibition using the photosensitizer verteporfin (VP) with and without light irradiation.

This thesis addresses this goal by (1) evaluating the effects of photodynamic priming (PDP) using VP on ATP depletion and its subsequent impact on P-gp function, (2) investigating how different formulations of VP influence its retention, subcellular localization, and ability to engage, evade, and exploit P-gp to enhance drug retention, and (3) examining the light-independent effects of VP on ATP depletion and sustained P-gp inhibition to improve chemotherapy efficacy in drug-resistant cancer cells.