A New Strategy of ALA-Photodynamic Cancer Therapy: Inhibition of ABC Transporter ABCG2

Abstract

Photodynamic therapy (PDT) is a clinical tool for treating various tumors. PDT is achieved by a photon-induced physicochemical reaction that is induced by excitation of porphyrins by exposure to light and the subsequent generation of singlet oxygen (1O2) and other reactive oxygen species. Recently, 5-aminolevulinic acid (ALA)-based PDT has been developed as an anticancer treatment whereby ALA is orally administered as the precursor of protoporphyrin IX (PpIX) to induce the biosynthesis and accumulation of PpIX in cancer cells. Recent studies, however, provide evidence that the ABC transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of PpIX in cancer cells and thereby affects the efficacy of ALA-based PDT. In response to the photoreaction of porphyrin leading to oxidative stress, the NF-E2-related transcription factor (Nrf2) can transcriptionally upregulate many target genes, including those for metabolizing enzymes and transporters essential for cellular defense. Whereas Nrf2 upregulates transcription of the ABCG2 gene to confer cancer cells resistance, several protein kinase inhibitors reportedly interfere with the transport function of ABCG2. In fact, gefitinib inhibits ABCG2-mediated porphyrin efflux from cancer cells to enhance the efficacy of PDT in vitro. Thus, it is of great interest to develop ABCG2-specific inhibitors that are clinically applicable to photodynamic cancer therapy. Hitherto, we have performed high-speed screening, quantitative structure–activity relationship (QSAR) analysis, and in vivo validation to identify potent ABCG2-inhibitors. This chapter addresses such a new approach to improve ALA-based photodynamic cancer therapy.