Mechanisms of photodynamic priming to overcome multidrug resistance

Efforts to combat cancer multidrug resistance (MDR) using small-molecule inhibitors of ATP-binding cassette (ABC) drug efflux transporters have faced limited success in clinical settings, primarily due to systemic toxicities. Photodynamic priming (PDP) has emerged as a promising strategy to inhibit ABC transporters, such as ABCB1 and ABCG2, without damaging normal tissues. Utilizing the verteporfin photosensitizer and a 690-nm laser, PDP has demonstrated the ability to reduce the function of ABCB1 and ABCG2 in membrane vesicle models, cancer cells, and tumors Mechanistic studies indicate that verteporfin binds to and directly induces photodamage of ABCB1 and ABCG2. PDP can also indirectly suppress ABCB1 function by affecting cellular respiration and reducing intracellular ATP levels. This work advances our understanding of PDP and its potential use to overcome MDR in cancer patients.