Transporter-Mediated Drug Interaction Strategy for 5-Aminolevulinic Acid (ALA)-Based Photodynamic Diagnosis of Malignant Brain Tumor: Molecular Design of ABCG2 Inhibitors

Toshihisa Ishikawa,Shin-Ichi Miyatake,Yuichiro Hagiya,Kenkichi Takahashi,Toshihiko Kuroiwa,Shun-Ichiro Ogura,Naokado Ikeda,Yoshinaga Kajimoto

doi:10.3390/pharmaceutics3030615

Abstract

Photodynamic diagnosis (PDD) is a practical tool currently used in surgical operation of aggressive brain tumors, such as glioblastoma. PDD is achieved by a photon-induced physicochemical reaction which is induced by excitation of protoporphyrin IX (PpIX) exposed to light. Fluorescence-guided gross-total resection has recently been developed in PDD, where 5-aminolevulinic acid (ALA) or its ester is administered as the precursor of PpIX. ALA induces the accumulation of PpIX, a natural photo-sensitizer, in cancer cells. Recent studies provide evidence that adenosine triphosphate (ATP)-binding cassette (ABC) transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of porphyrins in cancer cells and thereby affects the efficacy of PDD. Protein kinase inhibitors are suggested to potentially enhance the PDD efficacy by blocking ABCG2-mediated porphyrin efflux from cancer cells. It is of great interest to develop potent ABCG2-inhibitors that can be applied to PDD for brain tumor therapy. This review article addresses a pivotal role of human ABC transporter ABCG2 in PDD as well as a new approach of quantitative structure-activity relationship (QSAR) analysis to design potent ABCG2-inhibitors.

Highlights

In the 1960s Lipson and Baldes introduced a hematoporphyrin derivative (HpD), a product derived following treatment of hematoporphyrin with a mixture of acetic and sulfuric acids and sodium hydroxide [1]
photodynamic diagnosis (PDD) and photodynamic therapy (PDT) are achieved by a photon-induced physicochemical reaction which is induced by excitation of photosensitizer exposed to light
Photodynamic Diagnosis and Fluorescence-Guided Microsurgery In PDD and fluorescence-guided neurosurgery [9,10,12,15,16], aminolevulinic acid (ALA) is used for intra-operative labeling of the border regions of malignant gliomas infiltrated by alive clonogenic tumor cells and is helpful in precise resection of those regions

Summary

Introduction

In the 1960s Lipson and Baldes introduced a hematoporphyrin derivative (HpD), a product derived following treatment of hematoporphyrin with a mixture of acetic and sulfuric acids and sodium hydroxide [1]. Their development of the hematoporphyrin derivative established the basis of today’s photodynamic diagnosis (PDD) and photodynamic therapy (PDT) [2,3,4,5,6,7,8]. Because of its high tumor specificity and safety, ALA is promising It actively accumulates in the neoplasm and is converted to PpIX which is fluorescent. Fluorescence-guided resection is considered beneficial for the removal of complicated or malignant tumors that have a high risk of recurrence

Biosynthesis and Metabolism of Porphyrins and Heme

Photodynamic Diagnosis and Fluorescence-Guided Microsurgery

Human ABC Transporter ABCG2 in Cancer Chemotherapy and PDT

Hypothetical Mechanism Underlying ABCG2-Mediated PpIX Transport

Findings

Conclusions