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

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Resistance to Targeted ABC Transporters in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 4))

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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.

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Abbreviations

ALA:

5-Aminolevulinic acid

PDT:

Photodynamic therapy

PpIX:

Protoporphyrin IX

Nrf2:

NF-E2-related transcription factor

1O2 :

Singlet oxygen

ROS:

Reactive oxygen species

QSAR:

Quantitative structure-activity relationship

HO-1:

Hemeoxigenase

PKC:

Protein kinase C

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Acknowledgements

The authors thank Drs. Takehiro Fukami and Toshio Goto (RIKEN Program for Drug Discovery and Medical Technology Platforms, Japan) as well as Drs. Tohru Tanaka and Motowo Nakajima (SBI Pharma Inc. Japan) for their valuable advice and generous support. Studies in the authors’ laboratories were supported, in part, by a grant of Exploratory Research (No. 23650619 TI) from the Japanese Society for the Promotion of Science (JSPS) as well as by a Grant-in-Aid for Scientific Research (C) (No. 23592147 T.K.) and (B) (No. 23390355 S.-I.M.) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT).

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Authors and Affiliations

  1. NGO Personalized Medicine and Healthcare, 4-17-30 Kirigaoka, Midori-ku, Yokohama, 226-0016, Japan

    Toshihisa Ishikawa Ph.D.

  2. Department of Drug Metabolism and Disposition, Meiji Pharmaceutical University, Tokyo, 204-8588, Japan

    Yutaka Inoue & Yoji Ikegami

  3. Department of Neurosurgery, Osaka Medical College, Osaka, 569-8686, Japan

    Takahiro Fujishiro, Yoshinaga Kajimoto, Shin-Ichi Miyatake & Toshihiko Kuroiwa

  4. Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori, 680-8553, Japan

    Tomohiro Osaki

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  1. Toshihisa Ishikawa Ph.D.
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  1. Department of Pharmaceutical Biology, Johannes Gutenberg University, Mainz, Germany

    Thomas Efferth

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Ishikawa, T. et al. (2015). A New Strategy of ALA-Photodynamic Cancer Therapy: Inhibition of ABC Transporter ABCG2. In: Efferth, T. (eds) Resistance to Targeted ABC Transporters in Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 4. Springer, Cham. https://doi.org/10.1007/978-3-319-09801-2_4

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