The Effect of Iron Ion on the Specificity of Photodynamic Therapy with 5-aminolevulinic Acid

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Mar 31

PMID 25822972

Citations 11

Authors

Maiko Hayashi

Hideo Fukuhara

Keiji Inoue

Taro Shuin

Yuichiro Hagiya

Motowo Nakajima

Tohru Tanaka

Shun-Ichiro Ogura

Affiliations

Soon will be listed here.

Abstract

Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects.

Citing Articles

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5-aminolevulinic acid induced photodynamic reactions in diagnosis and therapy for female lower genital tract diseases.

Chen Y, Guo P, Chen L, He D Front Med (Lausanne). 2024; 11:1370396.

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Photodynamic Therapy for Bladder Cancers, A Focused Review.

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Synthesis and applications of [60]fullerene nanoconjugate with 5-aminolevulinic acid and its glycoconjugate as drug delivery vehicles.

Serda M, Gawecki R, Dulski M, Sajewicz M, Talik E, Szubka M RSC Adv. 2022; 12(11):6377-6388.

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5-Aminolevulinic acid overcomes hypoxia-induced radiation resistance by enhancing mitochondrial reactive oxygen species production in prostate cancer cells.

Owari T, Tanaka N, Nakai Y, Miyake M, Anai S, Kishi S Br J Cancer. 2022; 127(2):350-363.

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References

Ishizuka M, Hagiya Y, Mizokami Y, Honda K, Tabata K, Kamachi T . Porphyrins in urine after administration of 5-aminolevulinic acid as a potential tumor marker. Photodiagnosis Photodyn Ther. 2011; 8(4):328-31. DOI: 10.1016/j.pdpdt.2011.04.004. View

Krammer B, Plaetzer K . ALA and its clinical impact, from bench to bedside. Photochem Photobiol Sci. 2008; 7(3):283-9. DOI: 10.1039/b712847a. View

Rauen U, Springer A, Weisheit D, Petrat F, Korth H, de Groot H . Assessment of chelatable mitochondrial iron by using mitochondrion-selective fluorescent iron indicators with different iron-binding affinities. Chembiochem. 2007; 8(3):341-52. DOI: 10.1002/cbic.200600311. View

Yamamoto F, Ohgari Y, Yamaki N, Kitajima S, Shimokawa O, Matsui H . The role of nitric oxide in delta-aminolevulinic acid (ALA)-induced photosensitivity of cancerous cells. Biochem Biophys Res Commun. 2007; 353(3):541-6. DOI: 10.1016/j.bbrc.2006.12.007. View

Ohgari Y, Nakayasu Y, Kitajima S, Sawamoto M, Mori H, Shimokawa O . Mechanisms involved in delta-aminolevulinic acid (ALA)-induced photosensitivity of tumor cells: relation of ferrochelatase and uptake of ALA to the accumulation of protoporphyrin. Biochem Pharmacol. 2005; 71(1-2):42-9. DOI: 10.1016/j.bcp.2005.10.019. View

Choudry K, Brooke R, Farrar W, Rhodes L . The effect of an iron chelating agent on protoporphyrin IX levels and phototoxicity in topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol. 2003; 149(1):124-30. DOI: 10.1046/j.1365-2133.2003.05351.x. View

Paradkar P, Zumbrennen K, Paw B, Ward D, Kaplan J . Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2. Mol Cell Biol. 2008; 29(4):1007-16. PMC: 2643804. DOI: 10.1128/MCB.01685-08. View

Yoon T, Cowan J . Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem. 2004; 279(25):25943-6. DOI: 10.1074/jbc.C400107200. View

Mrozek-Wilczkiewicz A, Serda M, Musiol R, Malecki G, Szurko A, Muchowicz A . Iron chelators in photodynamic therapy revisited: synergistic effect by novel highly active thiosemicarbazones. ACS Med Chem Lett. 2014; 5(4):336-9. PMC: 4027794. DOI: 10.1021/ml400422a. View

10.

Tran T, Mu A, Adachi Y, Adachi Y, Taketani S . Neurotransmitter transporter family including SLC6A6 and SLC6A13 contributes to the 5-aminolevulinic acid (ALA)-induced accumulation of protoporphyrin IX and photodamage, through uptake of ALA by cancerous cells. Photochem Photobiol. 2014; 90(5):1136-43. DOI: 10.1111/php.12290. View

11.

Hagiya Y, Endo Y, Yonemura Y, Takahashi K, Ishizuka M, Abe F . Pivotal roles of peptide transporter PEPT1 and ATP-binding cassette (ABC) transporter ABCG2 in 5-aminolevulinic acid (ALA)-based photocytotoxicity of gastric cancer cells in vitro. Photodiagnosis Photodyn Ther. 2012; 9(3):204-14. DOI: 10.1016/j.pdpdt.2011.12.004. View

12.

Kennedy J, Pottier R, Pross D . Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B. 1990; 6(1-2):143-8. DOI: 10.1016/1011-1344(90)85083-9. View

13.

Agostinis P, Berg K, Cengel K, Foster T, Girotti A, Gollnick S . Photodynamic therapy of cancer: an update. CA Cancer J Clin. 2011; 61(4):250-81. PMC: 3209659. DOI: 10.3322/caac.20114. View

14.

Berg K, Anholt H, Bech O, Moan J . The influence of iron chelators on the accumulation of protoporphyrin IX in 5-aminolaevulinic acid-treated cells. Br J Cancer. 1996; 74(5):688-97. PMC: 2074689. DOI: 10.1038/bjc.1996.423. View

15.

Hagiya Y, Fukuhara H, Matsumoto K, Endo Y, Nakajima M, Tanaka T . Expression levels of PEPT1 and ABCG2 play key roles in 5-aminolevulinic acid (ALA)-induced tumor-specific protoporphyrin IX (PpIX) accumulation in bladder cancer. Photodiagnosis Photodyn Ther. 2013; 10(3):288-95. DOI: 10.1016/j.pdpdt.2013.02.001. View

16.

Sawamoto M, Imai T, Umeda M, Fukuda K, Kataoka T, Taketani S . The p53-dependent expression of frataxin controls 5-aminolevulinic acid-induced accumulation of protoporphyrin IX and photo-damage in cancerous cells. Photochem Photobiol. 2012; 89(1):163-72. DOI: 10.1111/j.1751-1097.2012.01215.x. View

17.

Dougherty T, Gomer C, Henderson B, Jori G, Kessel D, Korbelik M . Photodynamic therapy. J Natl Cancer Inst. 1998; 90(12):889-905. PMC: 4592754. DOI: 10.1093/jnci/90.12.889. View

18.

Chen A, Setser A, Anadkat M, Cotliar J, Olsen E, Garden B . Grading dermatologic adverse events of cancer treatments: the Common Terminology Criteria for Adverse Events Version 4.0. J Am Acad Dermatol. 2012; 67(5):1025-39. DOI: 10.1016/j.jaad.2012.02.010. View

19.

Inoue K, Ota U, Ishizuka M, Kawada C, Fukuhara H, Shuin T . Porphyrins as urinary biomarkers for bladder cancer after 5-aminolevulinic acid (ALA) administration: the potential of photodynamic screening for tumors. Photodiagnosis Photodyn Ther. 2013; 10(4):484-9. DOI: 10.1016/j.pdpdt.2013.05.002. View

20.

Serda M, Kalinowski D, Rasko N, Potuckova E, Mrozek-Wilczkiewicz A, Musiol R . Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships. PLoS One. 2014; 9(10):e110291. PMC: 4199632. DOI: 10.1371/journal.pone.0110291. View