Role of Nrf2 in Cancer Photodynamic Therapy: Regulation of Human ABC Transporter ABCG2

• Published in: Journal of pharmaceutical sciences Vol. 102; no. 9; pp. 3058 - 3069
• Main Authors: Ishikawa, Toshihisa, Kajimoto, Yoshinaga, Sun, Wei, Nakagawa, Hiroshi, Inoue, Yutaka, Ikegami, Yoji, Miyatake, Shin-Ichi, Kuroiwa, Toshihiko
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.09.2013; Wiley Subscription Services, Inc., A Wiley Company; Elsevier Limited
• Subjects: ABC transporters; aminolevulinic acid (ALA); Animals; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; cancer; gefitinib; Humans; metabolism; mRNA; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; oxidative stress; Photochemotherapy; Polymorphism, Single Nucleotide; porphyrin; Porphyrins - metabolism; Reactive Oxygen Species - metabolism; single nucleotide polymorphism (SNP); Transcriptional Activation; porphyrin; Nrf2; aminolevulinic acid (ALA); single nucleotide polymorphism (SNP); ABC transporters; cancer; gefitinib; metabolism; mRNA; oxidative stress
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.23563

Photodynamic therapy (PDT) is a recently developed anticancer treatment that utilizes the generation of singlet oxygen and other reactive oxygen species in cancer tissue. In response to oxidative stress, NF-E2-related transcription factor (Nrf2) encoded by the NFE2L2 gene plays a key role in transcriptional upregulation of many target genes, including those for metabolizing enzymes and transporters essential for cellular defense. Recent studies have provided evidence that Nrf2 regulates the transcription of the human ABC transporter ABCG2 gene, which is critically involved in the cellular accumulation of porphyrins in PDT. Nrf2 interacts with the antioxidant responsive element (ARE) located in the promoter region of human ABCG2 gene. Nrf2-specific siRNA treatments suppressed the induction of ABCG2 expression after the photoactivation of porphyrins in vitro. One SNP (−617C>A; rs6721961) in the ARE-like loci of the human Nrf2 gene is considered to affect the positive feedback loop of transcriptional activation of the Nrf2 gene as well as its target genes including ABCG2. Since patients have demonstrated individual differences in their response to PDT, Nrf2-mediated transcriptional activation of the ABCG2 gene in cancer may affect patients' responses to PDT as well as chemotherapy. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3058–3069, 2013