Inhibition of ABCG2 transporter by lapatinib enhances 5-aminolevulinic acid-mediated protoporphyrin IX fluorescence and photodynamic therapy response in human glioma cell lines
Open accessAbstract
5-Aminolevulinic acid (ALA) is an intraoperative molecular probe approved for fluorescence-guided resection (FGR) of high-grade gliomas to achieve maximal safe tumor resection. Although ALA has no fluorescence on its own, it is metabolized in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX) with red fluorescence for tumor detection and photosensitizing activity for photodynamic therapy (PDT). The preferential tumor accumulation of PpIX following ALA administration enables the use of ALA as a prodrug for PpIX FGR and PDT of gliomas. Since intracellular PpIX in tumor cells after ALA treatment is influenced by biological processes including PpIX bioconversion catalyzed by ferrochelatase (FECH) and PpIX efflux by ATP-binding cassette subfamily G member 2 (ABCG2), we determined the activity of FECH and ABCG2 in a panel of human glioma cell lines and correlated with intracellular and extracellular PpIX levels and PDT response. We found that glioma cell lines with ABCG2 activity exhibited the trend of low intracellular PpIX, high extracellular PpIX and low PDT response, whereas no particular correlation was seen with FECH activity. Inhibition of PpIX efflux with ABCG2 inhibitors was more effective in enhancing ALA-PpIX fluorescence and PDT response than blocking PpIX bioconversion with iron chelator deferoxamine. We also showed that a clinically used kinase inhibitor lapatinib could be repurposed for therapeutic enhancement of ALA due to its potent ABCG2 inhibitory activity. Our study reveals ABCG2 as an important biological determinant of PpIX fluorescence in glioma cells and suggests ABCG2 inhibition with lapatinib as a promising therapeutic enhancement approach.
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Lapatinib not only enhances PpIX fluorescence but also increases PpIX accumulation in mitochondria, which greatly potentiates PDT-induced cell death in tumor cells that are otherwise resistant to ALA-PDT.
“Notably, the tyrosine kinase inhibitor lapatinib not only enhances PpIX fluorescence but also increases PpIX accumulation in mitochondria, which greatly potentiates PDT-induced cell death in tumor cells that are otherwise resistant to ALA-PDT [105,128].”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [105]
The Results (page unavailable) report increased PpIX fluorescence and reduced cell viability after lapatinib-enhanced ALA-PDT in glioma cell lines, including H4 and U-87-IDH1 cells that resisted ALA-PDT alone. They measure increased intracellular PpIX, not specifically mitochondrial accumulation. The Discussion (page unavailable) treats intracellular localization as a possible explanation for differences in PDT response, not an established effect of lapatinib. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe effects of iron chelators on ALA-PpIX fluorescence are highly dependent on the cell line and ALA dose.
“It turns out that the effects of iron chelators on ALA-PpIX fluorescence are highly dependent on the cell line and ALA dose [85,88,92,105].”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [105]
The Results section on DFO and Ko143 (page unavailable) reports that the iron chelator DFO produced slight increases in ALA-PpIX fluorescence across the glioma cell lines, with a statistically significant increase only in U-118 cells. This supports a cell-line difference, but the paper does not show that the chelator’s effect on fluorescence depends on ALA dose; its ALA-dose results concern PDT response instead. (LLM, conf=0.85)
Experimental — accuracy not yet measuredChelator-induced PpIX enhancement is more pronounced at low doses of ALA than at the high doses of ALA that are typically used.
“Chelator-induced PpIX enhancement is more pronounced at low doses of ALA than at the high doses of ALA that are typically used.”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [105]
The Introduction (page unavailable) says iron chelators can increase ALA-induced PpIX fluorescence, and the Results (page unavailable) report slight increases with deferoxamine in glioma cell lines. Neither passage compares chelator-induced enhancement at low versus high ALA doses or establishes which doses are typically used. (LLM, conf=0.83)
Experimental — accuracy not yet measuredReduced 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 [105]
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References 42 · Cited by 38
Research works printed but not linked: 29
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- Authors
- Mansi, M., Howley, R., Chandratre, S., & Chen, B.
- Affiliations
- University of the Sciences (US)
- Corresponding author
- Chen, Bin
- ORCID
- Howley, Richard
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 200
- Pages
- 115031
- ISSN
- 0006-2952 (ISSN-L)
- PMC
- PMC10258830
- OpenAlex
- W4223474676
- Cited by
- 38
- References
- 42
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 16 · 2023: 9 · 2022: 1
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 309 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Biochemical Pharmacology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R15CA268200, R15EB026208)
- Foundation for the National Institutes of Health
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Keywords
- ABCG2, lapatinib, 5-aminolevulinic acid, protoporphyrin IX, photodynamic therapy, fluorescence-guided resection, glioma, ferrochelatase, deferoxamine, drug repurposing, heme biosynthesis, ABCG2 inhibitors
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Lapatinib, Aminolevulinic Acid, Ferrochelatase, Fluorescence, Glioma, Humans, Neoplasm Proteins, Photochemotherapy, Protoporphyrins, Photosensitizing Agents, Cell Line, Tumor
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