Effectiveness of lapatinib for enhancing 5-aminolevulinic acid-mediated protoporphyrin IX fluorescence and photodynamic therapy in human cancer cell lines with varied ABCG2 activities.

5-Aminolevulinic acid (ALA) is a prodrug for protoporphyrin IX (PpIX)-mediated photodynamic therapy (PDT) and fluorescence-guided tumor surgery. We previously reported that lapatinib, a repurposed ABCG2 inhibitor, enhanced ALA-induced PpIX fluorescence and PDT by blocking ABCG2-mediated PpIX efflux. In the present study, we evaluated how the variation in ABCG2 activities/protein levels affected tumor cell response to the enhancement of PpIX/PDT by lapatinib and Ko143, an ABCG2 tool inhibitor. ABCG2 activities and protein levels were determined in a panel of human cancer cell lines. Effects of lapatinib and Ko143 on enhancing ALA-PpIX fluorescence and PDT were evaluated and correlated with tumor cell ABCG2 activities. We found that both lapatinib and Ko143 enhanced ALA-PpIX fluorescence and PDT in a dose-dependent manner, although lapatinib exhibited lower efficacy and potency than Ko143 in nearly all cancer cell lines. The EC50 of ABCG2 inhibitors for enhancing ALA-PpIX and PDT had a positive correlation with tumor cell ABCG2 activities, indicating that tumor cell lines with lower ABCG2 activities were more sensitive to ABCG2 inhibitors for PpIX/PDT enhancement. Our results suggest that, for optimal therapeutic enhancement, the dose of ABCG2 inhibitors needs to be tailored based on the ABCG2 expression/activity in tumors.

Targeting ABCG2 transporter to enhance 5-aminolevulinic acid for tumor visualization and photodynamic therapy.

5-Aminolevulinic acid (ALA) has been approved by the U. S. FDA for fluorescence-guided resection of high-grade glioma and photodynamic therapy (PDT) of superficial skin precancerous and cancerous lesions. As a prodrug, ALA administered orally or topically is metabolized in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX), the active drug with red fluorescence and photosensitizing property. Preferential accumulation of PpIX in tumors after ALA administration enables the use of ALA for PpIX-mediated tumor fluorescence diagnosis and PDT, functioning as a photo-theranostic agent. Extensive research is currently underway to further enhance ALA-mediated PpIX tumor disposition for better tumor visualization and treatment. Particularly, the discovery of PpIX as a specific substrate of ATP binding cassette subfamily G member 2 (ABCG2) opens the door to therapeutic enhancement with ABCG2 inhibitors. Studies with human tumor cell lines and human tumor samples have demonstrated ABCG2 as an important biological determinant of reduced ALA-PpIX tumor accumulation, inhibition of which greatly enhances ALA-PpIX fluorescence and PDT response. These studies strongly support targeting ABCG2 as an effective therapeutic enhancement approach. In this review, we would like to summarize current research of ABCG2 as a drug efflux transporter in multidrug resistance, highlight previous works on targeting ABCG2 for therapeutic enhancement of ALA, and provide future perspectives on how to translate this ABCG2-targeted therapeutic enhancement strategy from bench to bedside.