Skip to main content

Advertisement

SpringerLink
Log in

Key transporters leading to specific protoporphyrin IX accumulation in cancer cell following administration of aminolevulinic acid in photodynamic therapy/diagnosis

  • Invited Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

The administration of aminolevulinic acid allow the formation and accumulation of protoporphyrin IX specifically in cancer cells, which then lead to photocytotoxicity following light irradiation. This compound, when accumulated at high levels, could also be used in cancer diagnosis as it would emit red fluorescence when being light irradiated. The concentration of protoporphyrin IX is pivotal in ensuring the effectiveness of the therapy. Studies have been carried out and showed the importance of various transporters in regulating the amount of these substrates by controlling the transport of various related metabolites in and out of the cell. There are many transporters involved and their expression levels are dependent on various factors, such as oxygen availability and iron ions. It is also important to note that these transporters may also have different expression levels depending on their organ. Understanding the mechanisms and the roles of these transporters are essential to ensure maximum accumulation of protoporphyrin IX, leading to higher efficiency in photodynamic therapy/diagnosis. In this review, we would like to discuss the roles of various transporters in protoporphyrin IX accumulation and how their involvement directly affect cancerous microenvironment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Moan J, Peng Q (2003) An outline of the hundred-year history of PDT. Anticancer Res 23:3591–3600

    PubMed  Google Scholar 

  2. Itoh Y, Ninomiya Y, Tajima S et al (2001) Photodynamic therapy of acne vulgaris with topical δ-aminolaevulinic acid and incoherent light in Japanese patients. Brit J Dermatol 144(3):575–579

    CAS  Google Scholar 

  3. Dolmans DE, Fukumura D, Jain RK (2003) Photodynamic therapy for cancer. Nat Rev Cancer 3(5):380

    CAS  PubMed  Google Scholar 

  4. Peng Q, Warloe T, Berg K et al (1997) 5-Aminolevulinic acid-based photodynamic therapy. Cancer 79(12):2282–2308

    CAS  PubMed  Google Scholar 

  5. Van Hillegersberg R, Van Den Berg JWO, Kort WJ et al (1992) Selective accumulation of endogenously produced porphyrins in a liver metastasis model in rats. Gastroenterology 103:647–651

    PubMed  Google Scholar 

  6. Yang X, Palasuberniam P, Kraus D et al (2015) Aminolevulinic acid-based tumor detection and therapy: molecular mechanisms and strategies for enhancement. Int J Mol Sci 16:25865–25880. https://doi.org/10.3390/ijms161025865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. De Rosa FS, Bentley MVL (2000) Photodynamic therapy of skin cancers: sensitizers, clinical studies and future directives. Pharm Res 17(12):1447–1455

    PubMed  Google Scholar 

  8. Stummer W, Pichlmeier U, Meinel T et al (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Onco 7(5):392–401

    CAS  Google Scholar 

  9. Ennis SR, Novotny A, Xiang J et al (2003) Transport of 5-aminolevulinic acid between blood and brain. Brain Res 959(2):226–234

    CAS  PubMed  Google Scholar 

  10. Collaud S, Juzeniene A, Moan J et al (2004) On the selectivity of 5-aminolevulinic acid-induced protoporphyrin IX formation. Curr Med Chem 4(3):301–316

    CAS  Google Scholar 

  11. Valdés PA, Leblond F, Kim A et al (2011) Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. J Neurosurg 115(1):11–17

    PubMed  PubMed Central  Google Scholar 

  12. Ito H, Kurokawa H, Suzuki H et al (2019) 5-Aminolevulinic acid induced apoptosis via oxidative stress in normal gastric epithelial cells. J Clin Biochem Nutr 65(2):83–90. https://doi.org/10.3164/jcbn.18-46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Smith DE, Clémençon B, Hediger MA (2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Aspects Med 34:323–336. https://doi.org/10.1016/j.mam.2012.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Thwaites DT, Anderson CMH (2007) Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. BBA-Biomembranes 1768:179–197. https://doi.org/10.1016/j.bbamem.2006.10.001

    Article  CAS  PubMed  Google Scholar 

  15. Kristensen AS, Andersen J, Jørgensen TN et al (2011) SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev 63:585–640. https://doi.org/10.1124/pr.108.000869

    Article  CAS  PubMed  Google Scholar 

  16. Teng L, Nakada M, Zhao SG et al (2011) Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy. Brit J Cancer 104(5):798–807

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Safi R, Mohsen-Kanson T, Nemer G et al (2019) Loss of ferrochelatase is protective against colon cancer cells: ferrochelatase a possible regulator of the long noncoding RNA H19. J Gastrointest Oncol 10(5):859

    PubMed  PubMed Central  Google Scholar 

  18. Rhodes LE, Tsoukas MM, Anderson RR et al (1997) Iontophoretic delivery of ALA provides a quantitative model for ALA pharmacokinetics and PpIX phototoxicity in human skin. J Invest Dermatol 108(1):87–91

    CAS  PubMed  Google Scholar 

  19. Lathrop JT, Timko MP (1993) Regulation by heme of mitochondrial protein transport through a conserved amino acid motif. Science 259(5094):522–525

    CAS  PubMed  Google Scholar 

  20. Frank J, Lornejad-Schäfer MR, Schöffl H et al (2007) Inhibition of heme oxygenase-1 increases responsiveness of melanoma cells to ALA-based photodynamic therapy. Int J Oncol 31(6):1539–1545

    CAS  PubMed  Google Scholar 

  21. Hagiya Y, Adachi T, Ogura SI et al (2008) Nrf2-dependent induction of human ABC transporter ABCG2 and heme oxygenase-1 in HepG2 cells by photoactivation of porphyrins: biochemical implications for cancer cell response to photodynamic therapy. J Exp Ther Oncol 7:2

    Google Scholar 

  22. Hagiya Y, Endo Y, Yonemura Y et al (2012) 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. Photodiagn Photodyn 9(3):204–214

    CAS  Google Scholar 

  23. Khan AA, Quigley JG (2013) Heme and FLVCR-related transporter families SLC48 and SLC49. Mol Aspects Med 34(2–3):669–682

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chavan H, Khan MMT, Tegos G et al (2013) Efficient purification and reconstitution of ATP binding cassette transporter B6 (ABCB6) for functional and structural studies. J Biol Chem 288(31):22658–22669

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wyld L, Reed MWR, Brown NJ (1998) The influence of hypoxia and pH on aminolaevulinic acid-induced photodynamic therapy in bladder cancer cells in vitro. Brit J Cancer 77(10):1621–1627

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakayama T, Otsuka S, Kobayashi T et al (2016) Dormant cancer cells accumulate high protoporphyrin IX levels and are sensitive to 5-aminolevulinic acid-based photodynamic therapy. Sci Rep-UK 6:36478

    CAS  Google Scholar 

  27. Blake E, Curnow A (2010) The hydroxypyridinone iron chelator CP94 can enhance PpIX-induced PDT of cultured human glioma cells. Photochem Photobiol 86(5):1154–1160

    CAS  PubMed  Google Scholar 

  28. Anderson CM, Jevons M, Thangaraju M et al (2010) Transport of the photodynamic therapy agent 5-aminolevulinic acid by distinct H+-coupled nutrient carriers coexpressed in the small intestine. J Pharmacol Exp Ther 332(1):220–228

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Rubio-Aliaga I, Daniel H (2002) Mammalian peptide transporters as targets for drug delivery. Trends Pharmacol Sci 23(9):434–440

    CAS  PubMed  Google Scholar 

  30. Addison JM, Burston D, Dalrymple JA et al (1975) A common mechanism for transport of di-and tri-peptides by Hamster Jejunum in vitro. Clin Sci 49(4):313–322

    CAS  Google Scholar 

  31. Adibi SA, Morse EL (1977) The number of glycine residues which limits intact absorption of glycine oligopeptides in human jejunum. J Clin Invest 60(5):1008–1016

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Döring F, Walter J, Will J et al (1998) Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications. J Clin Invest 101(12):2761–2767

    PubMed  PubMed Central  Google Scholar 

  33. Novotny A, Xiang J, Stummer W et al (2000) Mechanisms of 5-aminolevulinic acid uptake at the choroid plexus. J Neurochem 75(1):321–328

    CAS  PubMed  Google Scholar 

  34. Rodriguez L, Batlle A, Di Venosa G et al (2006) Study of the mechanisms of uptake of 5-aminolevulinic acid derivatives by PEPT1 and PEPT2 transporters as a tool to improve photodynamic therapy of tumours. Int J Biochem Cell B 38(9):1530–1539

    CAS  Google Scholar 

  35. Boll M, Foltz M, Rubio-Aliaga I et al (2002) Functional characterization of two novel mammalian electrogenic proton-dependent amino acid cotransporters. J Biol Chem 277(25):22966–22973

    CAS  PubMed  Google Scholar 

  36. Chen Z, Fei YJ, Anderson CM et al (2003) Structure, function and immunolocalization of a proton-coupled amino acid transporter (hPAT1) in the human intestinal cell line Caco-2. J Physiol 546(2):349–361

    CAS  PubMed  Google Scholar 

  37. Frølund S, Marquez OC, Larsen M et al (2010) δ-Aminolevulinic acid is a substrate for the amino acid transporter SLC36A1 (hPAT1). Brit J Pharmacol 159(6):1339–1353

    Google Scholar 

  38. Meredith D, Temple CS, Guha N et al (2000) Modified amino acids and peptides as substrates for the intestinal peptide transporter PepT1. FEBS J 267(12):3723–3728

    CAS  Google Scholar 

  39. Xie Y, Hu Y, Smith DE (2016) The proton-coupled oligopeptide transporter 1 plays a major role in the intestinal permeability and absorption of 5-aminolevulinic acid. Brit J Pharmacol 173(1):167–176

    CAS  Google Scholar 

  40. Lai HW, Sasaki R, Usuki S et al (2019) Novel strategy to increase specificity of ALA-Induced PpIX accumulation through inhibition of transporters involved in ALA uptake. Photodiag Photodyn 27:327–335

    CAS  Google Scholar 

  41. Gether U, Andersen PH, Larsson OM et al (2006) Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol Sci 27(7):375–383

    CAS  PubMed  Google Scholar 

  42. Tomi M, Tajima A, Tachikawa M et al (2008) Function of taurine transporter (Slc6a6/TauT) as a GABA transporting protein and its relevance to GABA transport in rat retinal capillary endothelial cells. BBA-Biomembranes 1778(10):2138–2142

    CAS  PubMed  Google Scholar 

  43. Moretti MB, Garcia SC, Perotti C et al (2002) δ-aminolevulinic acid transport in murine mammary adenocarcinoma cells is mediated by BETA transporters. Brit J Cancer 87(4):471–474

    Google Scholar 

  44. Tran TT, Mu A, Adachi Y et al (2014) 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 90(5):1136–1143

    CAS  PubMed  Google Scholar 

  45. Tai W, Chen Z, Cheng K (2013) Expression profile and functional activity of peptide transporters in prostate cancer cells. Mol Pharm 10(2):477–487

    CAS  PubMed  Google Scholar 

  46. Yoshida A, Bu Y, Qie S et al (2019) SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors. Sci Adv 5(9):6352

    Google Scholar 

  47. Kriegmair M, Ehsan A, Baumgartner R et al (1994) Fluorescence photodetection of neoplastic urothelial lesions following intravesical instillation of 5-aminolevulinic acid. Urology 44(6):836–841

    CAS  PubMed  Google Scholar 

  48. Zaak D, Frimberger D, Stepp H et al (2001) Quantification of 5-aminolevulinic acid induced fluorescence improves the specificity of bladder cancer detection. J Urology 166(5):1665–1669

    CAS  Google Scholar 

  49. Smith DE, Clémençon B, Hediger MA (2013) Proton-coupled oligopeptide transporter family SLC15: Physiological, pharmacological and pathological implications. Mol Aspects Med 34(2–3):323–336

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Thwaites DT, Anderson CMH (2007) Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. BBA-Biomembrane 1768(2):179–197

    CAS  Google Scholar 

  51. Ishikawa T, Nakagawa H, Hagiya Y et al (2010) Key role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis. Adv Pharmacol Sci 2010:587306

    PubMed  PubMed Central  Google Scholar 

  52. Hagiya Y, Fukuhara H, Matsumoto K et al (2013) Expression levels of PEPT1 and ABCG2 play key roles in 5-aminolevulinic acid (ALA)-induced tumor-specific protoporphyrin IX (PpIX) accumulation in bladder cancer. Photodiag Photodyn 10:288–295

    CAS  Google Scholar 

  53. Ishizuka M, Hagiya Y, Mizokami Y et al (2011) Porphyrins in urine after administration of 5-aminolevulinic acid as a potential tumor marker. Photodiag Photodyn 8:328–331

    CAS  Google Scholar 

  54. Inoue K, Ota U, Ishizuka M et al (2013) Porphyrins as urinary biomarkers for bladder cancer after 5-aminolevulinic acid (ALA) administration: the potential of photodynamic screening for tumors. Photodiag Photodyn 10:484–489

    CAS  Google Scholar 

  55. Ota U, Fukuhara H, Ishizuka M et al (2015) Plasma protoporphyrin IX following administration of 5-aminolevulinic acid as a potential tumor marker. Mol Clin Oncol 3:797–801

    PubMed  PubMed Central  Google Scholar 

  56. Krishnamurthy PC, Du GQ, Fukuda Y et al (2006) Identification of a mammalian mitochondrial porphyrin transporter. Nature 443:586–589

    CAS  PubMed  Google Scholar 

  57. Matsumoto K, Hagiya Y, Endo Y et al (2015) Effects of plasma membrane ABCB6 on 5-aminolevulinic acid (ALA)-induced porphyrin accumulation in vitro: tumor cell response to hypoxia. Photodiag Photodyn 12:45–51

    CAS  Google Scholar 

  58. Ohgari Y, Nakayasu Y, Kitajima S et al (2005) Mechanisms involved in δ-aminolevulinic acid (ALA)-induced photosensitivity of tumor cells: relation of ferrochelatase and uptake of ALA to the accumulation of protoporphyrin. Biochem Pharmacol 71:121–345

    Google Scholar 

  59. Yamamoto F, Ohgari Y, Yamaki Y et al (2007) The role of nitric oxide in δ-aminolevulinic acid (ALA)-induced photosensitivity of cancerous cells. Biochem Biophys Res Commun 5:353

    Google Scholar 

  60. Paradkar P, Zumbrennen K, Paw B et al (2009) Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2. Mol Cell Biol 7:29

    Google Scholar 

  61. Ohgari Y, Miyata T, Miyagi S et al (2011) Roles of porphyrin and iron metabolisms in the δ-aminolevulinic acid (ALA)-induced accumulation of protoporphyrin and photodamage of tumor cells. Photochem Photobiol 1:87–128

    Google Scholar 

  62. Yoon T, Cowan J (2004) Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem 6:279

    Google Scholar 

  63. Hayashi M, Fukuhara H, Inoue K et al (2015) The effect of iron ion on the specificity of photodynamic therapy with 5-aminolevulinic acid. PLoS ONE 10:e0122351. https://doi.org/10.1371/journal.pone.0122351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564

    CAS  PubMed  Google Scholar 

  65. Wenzel C (2014) 3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions. Exp Cell Res 323:131–143

    CAS  PubMed  Google Scholar 

  66. Kyle AH, Baker JH, Minchinton AI (2012) Targeting quiescent tumor cells via oxygen and IGF-I supplementation. Cancer Res 72(3):801–809

    CAS  PubMed  Google Scholar 

  67. Endo H (2014) Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia. PLoS ONE 9:e98858

    PubMed  PubMed Central  Google Scholar 

  68. Pampaloni F, Reynaud EG, Stelzer EH (2007) The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol 8(10):839–845

    CAS  PubMed  Google Scholar 

  69. Ramaiahgari S (2014) A 3D in vitro model of differentiated HepG2 cell spheroids with improved liver like properties for repeated dose high throughput toxicity studies. Arch Toxicol 88:1083–1095

    CAS  PubMed  Google Scholar 

  70. Leontieva O (2014) Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program. Proc Natl Acad Sci 111:8832–8837

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Nakayama H, Okajima T, Kobayashi S et al (2016) Intracellular heme increases in a manner dependent on cell density. ALA-Porphyrin Science 4:13–17

    Google Scholar 

  72. Nakayama T, Nozawa N, Kawada C et al (2020) Mitomycin C-induced cell cycle arrest enhances 5-aminolevulinic acid-based photodynamic therapy for bladder cancer. Photodiag Photodyn 1:101893. https://doi.org/10.1016/j.pdpdt.2020.101893

    Article  CAS  Google Scholar 

  73. Yoshioka E, Chelakkot VS, Licursi M et al (2018) Enhancement of cancer-specific protoporphyrin ix fluorescence by targeting oncogenic ras/MEK pathway. Theranostics 8:2134–2146. https://doi.org/10.7150/thno.22641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chelakkot VS, Som J, Yoshioka E et al (2019) Systemic MEK inhibition enhances the efficacy of 5-aminolevulinic acid-photodynamic therapy. Brit J Cancer 121:758–767. https://doi.org/10.1038/s41416-019-0586-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nakayama T, Kobayashi T, Otsuka S et al (2019) Photodiagnosis and photodynamic therapy photoirradiation after aminolevulinic acid treatment suppresses cancer cell proliferation through the HO-1/p21 pathway. Photodiag Photodyn 28:10–17. https://doi.org/10.1016/j.pdpdt.2019.07.021

    Article  CAS  Google Scholar 

Download references

Funding

These studies in the author’s laboratories were supported by the Grant-in-Aid for Scientific Research (C) (No. 18K05332) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan. HWL is a MEXT scholar.

Author information

Authors and Affiliations

  1. School of Life Science and Technology, Tokyo Institute of Technology, 4259 B47, Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan

    Hung Wei Lai, Taku Nakayama & Shun-ichiro Ogura

  2. Center for Photodynamic Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku-shi, Kochi, 783-8505, Japan

    Taku Nakayama & Shun-ichiro Ogura

Authors
  1. Hung Wei Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Taku Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shun-ichiro Ogura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HWL, TN and SO collected information from various sources. HWL, TN and SO wrote the manuscript. HWL was involved in compiling, formatting and proofreading of the paper.

Corresponding author

Correspondence to Shun-ichiro Ogura.

Ethics declarations

Conflict of interest

All authors declared no conflict of interest. All authors agreed and approved the final manuscript for publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lai, H.W., Nakayama, T. & Ogura, Si. Key transporters leading to specific protoporphyrin IX accumulation in cancer cell following administration of aminolevulinic acid in photodynamic therapy/diagnosis. Int J Clin Oncol 26, 26–33 (2021). https://doi.org/10.1007/s10147-020-01766-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-020-01766-y

Keywords

Search

Navigation