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Cited by 25Photodynamic Therapy Research StudiesPorphyrin Metabolism and DisordersNanoplatforms for cancer theranostics

Evaluation of aminolevulinic acid-mediated protoporphyrin IX fluorescence and enhancement by ABCG2 inhibitors in renal cell carcinoma cells

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Howley, Richard, Mansi, Matthew, Shinde, Janhavi, Restrepo, Juliana, Chen, Bin·2020·Journal of Photochemistry and Photobiology B: Biology
DOI 10.1016/j.jphotobiol.2020.112017PMC PMC7545695
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Abstract

Aminolevulinic acid (ALA) has been approved as an intraoperative molecular imaging probe for protoporphyrin IX (PpIX) fluorescence-guided resection of glioma. Here we explored its potential application for renal cell carcinoma (RCC) that is showing increased incidence in recent years. ALA-mediated PpIX in cell lysates (intracellular) and culture medium was measured in five human RCC cell lines (786-O, 769-P, A-704, Caki-1, Caki-2) and a non-tumor human kidney epithelial cell line HK-2 by spectrofluorometry and flow cytometry. The activity of PpIX bioconversion enzyme ferrochelatase (FECH) and PpIX efflux transporter ABCG2 was determined to correlate with the PpIX level. We found that ALA-PpIX fluorescence was highly variable among RCC cell lines and A-704 was the only RCC cell line exhibiting significantly higher intracellular PpIX than HK-2 cells. Neither the intracellular PpIX level nor the total amount of PpIX (including PpIX in cell lysates and the medium) had significant correlation with the activity of FECH or ABCG2. To enhance the intracellular PpIX, cells were treated with Ko143, a pharmacological inhibitor of ABCG2. Ko143 significantly increased the intracellular PpIX in cell lines with ABCG2 activity, but not in cell lines with little ABCG2 activity. In fact, there was a positive correlation between the ABCG2 activity and Ko143-induced PpIX enhancement across kidney cell lines. To identify clinically relevant ABCG2 inhibitors, small molecule inhibitors targeting various cell signaling pathways, some of which are known to inhibit ABCG2, were evaluated for the enhancement of ALA-PpIX in Caki-2 cells that had the highest ABCG2 activity in the RCC cell panel. Our screening led to the identification of several clinically available inhibitors that significantly increased the intracellular PpIX. Particularly, kinase inhibitor lapatinib exhibited the strongest enhancement effect. These clinical inhibitors can be used for the enhancement of ALA-PpIX fluorescence in tumors with elevated ABCG2 activity.

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  • Reduced tumor FECH activity is so far the most common answer to the question of the biological basis of selective ALA-induced PpIX tumor disposition, although recent studies have failed to establish a correlation between tumor PpIX levels and FECH or any particular heme biosynthesis enzyme and porphyrin transporter.

    “Reduced tumor FECH activity is so far the most common answer to this question, although recent studies have failed to establish a correlation between tumor PpIX levels and FECH or any particular heme biosynthesis enzyme and porphyrin transporter [105,127,166].”

    From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [127]

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  • Ko143 is able to significantly enhance ALA-PpIX fluorescence in different human tumor cell lines including skin, bladder, breast, kidney, and brain tumors.

    “Ko143 is able to significantly enhance ALA-PpIX fluorescence in different human tumor cell lines including skin, bladder, breast, kidney, and brain tumors [122,123,124,125,126,127].”

    From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [127]

  • We have screened some small molecule inhibitors in a kidney cancer cell line with robust ABCG2 activity and found six FDA-approved drugs (lapatinib, gefitinib, sunitinib, vismodegib, vemurafenib, and sorafenib) that significantly enhance intracellular ALA-PpIX fluorescence.

    “We have screened some small molecule inhibitors in a kidney cancer cell line with robust ABCG2 activity and found six FDA-approved drugs (lapatinib, gefitinib, sunitinib, vismodegib, vemurafenib, and sorafenib) that significantly enhance intracellular ALA-PpIX fluorescence [127].”

    From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [127]

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Cited by

Sorted by citations

Authors
Howley, R., Mansi, M., Shinde, J., Restrepo, J., & Chen, B.
Affiliations
University of the Sciences (US)
Corresponding author
Chen, Bin
ORCID
Howley, Richard
Venue
Journal of Photochemistry and Photobiology B: Biology
Publisher
Elsevier BV
Published
2020-10
Volume
211
Pages
112017
ISSN
1011-1344 (ISSN-L)
DOI
10.1016/j.jphotobiol.2020.112017
PMC
PMC7545695
OpenAlex
W3083390359
Cited by
25
References
9
Citations by year
2026: 2 · 2025: 5 · 2024: 7 · 2023: 3 · 2022: 6 · 2021: 2
FWCI
1.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Photochemistry and Photobiology B Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (R15EB026208)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
  • Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
Keywords
5-aminolevulinic acid, protoporphyrin IX, ABCG2, renal cell carcinoma, Ko143, lapatinib, ferrochelatase, fluorescence-guided resection, ABCG2 inhibitors, small molecule inhibitor screening, Caki-2 cells, HK-2 cells
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 2, Lapatinib, Aminolevulinic Acid, Antineoplastic Agents, Biological Transport, Carcinoma, Renal Cell, Drug Screening Assays, Antitumor, Ferrochelatase, Humans, Kidney Neoplasms, Photochemotherapy, Protoporphyrins, Signal Transduction, Photosensitizing Agents, Cell Line, Tumor

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