Inhibition of ABCG2 transporter by lapatinib enhances 5-aminolevulinic acid-mediated protoporphyrin IX fluorescence and photodynamic therapy response in human glioma cell lines

Mansi, Matthew; Howley, Richard; Chandratre, Sharayu; Chen, Bin

doi:10.1016/j.bcp.2022.115031

Cited by 25 publications

(19 citation statements)

References 40 publications

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“…Thus, future research should aim at altering proteins of that pathway. Besides possibilities of highly targeted interventions via small molecule inhibitors or other means of gene knockdown like RNA interference, the already clinically approved tyrosine kinase inhibitor lapatinib has recently been shown to alter heme metabolism and thus constitutes a promising candidate for further research ( Smyth et al, 2019 ; Howley et al, 2020 ; Mansi et al, 2022 ). While extensive cell and molecular biology studies will be necessary to investigate the benefit of such therapies in glioma patients, the research presented in this study provides an important first step to guide heme biosynthesis-based therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

The impact of heme biosynthesis regulation on glioma aggressiveness: Correlations with diagnostic molecular markers

Mischkulnig

Kiesel

Rötzer-Pejrimovsky

et al. 2022

Front. Mol. Neurosci.

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BackgroundThe prognosis of diffusely infiltrating glioma patients is dismal but varies greatly between individuals. While characterization of gliomas primarily relied on histopathological features, molecular markers increasingly gained importance and play a key role in the recently published 5th edition of the World Health Organization (WHO) classification. Heme biosynthesis represents a crucial pathway due to its paramount importance in oxygen transport, energy production and drug metabolism. Recently, we described a “heme biosynthesis mRNA expression signature” that correlates with histopathological glioma grade and survival. The aim of the current study was to correlate this heme biosynthesis mRNA expression signature with diagnostic molecular markers and investigate its continued prognostic relevance.Materials and methodsIn this study, patient data were derived from the “The Cancer Genome Atlas” (TCGA) lower-grade glioma and glioblastoma cohorts. We identified diffusely infiltrating gliomas correlating molecular tumor diagnosis according to the most recent WHO classification with heme biosynthesis mRNA expression. The following molecular markers were analyzed: EGFR amplification, TERT promoter mutation, CDKN2A/B homozygous loss, chromosome 7 + /10- aneuploidy, MGMT methylation, IDH mutation, ATRX loss, p53 mutation and 1p19q codeletion. Subsequently, we calculated the heme biosynthesis mRNA expression signature for correlation with distinct molecular glioma markers/molecular subgroups and performed survival analyses.ResultsA total of 649 patients with available data on up-to-date molecular markers and heme biosynthesis mRNA expression were included. According to analysis of individual molecular markers, we found a significantly higher heme biosynthesis mRNA expression signature in gliomas with IDH wildtype (p < 0.0005), without 1p19q codeletion (p < 0.0005), with homozygous CDKN2A/B loss (p < 0.0005) and with EGFR amplification (p = 0.001). Furthermore, we observed that the heme biosynthesis mRNA expression signature increased with molecular subgroup aggressiveness (p < 0.0005), being lowest in WHO grade 2 oligodendrogliomas and highest in WHO grade 4 glioblastomas. Finally, the heme biosynthesis mRNA expression signature was a statistically significant survival predictor after multivariate correction for all molecular markers (p < 0.0005).ConclusionOur data demonstrate a significant correlation between heme biosynthesis regulation and diagnostic molecular markers and a prognostic relevance independent of these established markers. Consequently, heme biosynthesis expression is a promising biomarker for glioma aggressiveness and might constitute a potential target for novel therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

The impact of heme biosynthesis regulation on glioma aggressiveness: Correlations with diagnostic molecular markers

Mischkulnig

Kiesel

Rötzer-Pejrimovsky

et al. 2022

Front. Mol. Neurosci.

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“…Despite these promising results from many in vitro studies, EDTA does not increase PpIX production in a mouse tumor model [ 102 ] and BCC patients [ 103 ] after ALA administration, and DFO does not enhance PpIX fluorescence in skin cancer patients either [ 104 ]. 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 ]. While some cell lines are sensitive to PpIX enhancement by chelators, others are not.…”

Section: Strategies For Enhancing Ala-ppix Fluorescence and Ala-pdt R...mentioning

confidence: 99%

“…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 ]. 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 ]. These results indicate that repurposing lapatinib or other existing drugs as potential ABCG2 inhibitors is a promising and practical strategy for enhancing ALA-PpIX fluorescence and PDT.…”

Section: Strategies For Enhancing Ala-ppix Fluorescence and Ala-pdt R...mentioning

confidence: 99%

“…Furthermore, the question regarding the biological basis of selective ALA-induced PpIX tumor disposition is yet to be addressed. 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 ]. It is likely that enhanced ALA-PpIX in tumors is a polygenic tumor phenotype determined by a group of metabolic pathways.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy

2023

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5-Aminolevulinic acid (ALA) is a naturally occurring amino acid synthesized in all nucleated mammalian cells. As a porphyrin precursor, ALA is metabolized in the heme biosynthetic pathway to produce protoporphyrin IX (PpIX), a fluorophore and photosensitizing agent. ALA administered exogenously bypasses the rate-limit step in the pathway, resulting in PpIX accumulation in tumor tissues. Such tumor-selective PpIX disposition following ALA administration has been exploited for tumor fluorescence diagnosis and photodynamic therapy (PDT) with much success. Five ALA-based drugs have now received worldwide approval and are being used for managing very common human (pre)cancerous diseases such as actinic keratosis and basal cell carcinoma or guiding the surgery of bladder cancer and high-grade gliomas, making it the most successful drug discovery and development endeavor in PDT and photodiagnosis. The potential of ALA-induced PpIX as a fluorescent theranostic agent is, however, yet to be fully fulfilled. In this review, we would like to describe the heme biosynthesis pathway in which PpIX is produced from ALA and its derivatives, summarize current clinical applications of ALA-based drugs, and discuss strategies for enhancing ALA-induced PpIX fluorescence and PDT response. Our goal is two-fold: to highlight the successes of ALA-based drugs in clinical practice, and to stimulate the multidisciplinary collaboration that has brought the current success and will continue to usher in more landmark advances.

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“…Besides, ABCG2, an efflux transporter present in mitochondria as well as cell membranes, is able to induce extracellular transport of PpIX synthesized in mitochondria (Kobuchi et al, 2012). Therefore, to improve the accumulation of PpIX in cells can generally be achieved by 1) enhancing the activities of CPOX by using upregulated molecules such as methotrexate (MTX) and vitamin D (Ortel et al, 2002;Sinha et al, 2006); 2) using Fe 2+ chelators such as 1,2-diethyl-3-hydroxypyridin-4-one hydrochloride (CP94) or deferoxamine (DFO) to lower the conversion of PpIX to Heme (Richardson et al, 1994;Pye and Curnow, 2007); and 3) using ABCG2 inhibitors such as Fumitremorgin C (Robey et al, 2005), Ko143 (Palasuberniam et al, 2015), sunitinib (Mansi et al, 2022) or gefitinib (Palasuberniam et al, 2021) to reduce PpIX efflux.…”

Section: Introductionmentioning

confidence: 99%

Amplifying the efficacy of ALA-based prodrugs for photodynamic therapy using nanotechnology

et al. 2023

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5-aminolevulinic acid (ALA) is a clinically approved prodrug involved in intracellular Heme biosynthesis to produce the natural photosensitizer (PS) Protoporphyrin IX (PpIX). ALA based photodynamic therapy (PDT) has been used to treat various malignant and non-malignant diseases. However, natural ALA has disadvantages such as weak lipophilicity, low stability and poor bioavailability, greatly reducing its clinical performance. The emerging nanotechnology is expected to address these limitations and thus improve the therapeutic outcomes. Herein, we summarized important recent advances in the design of ALA-based prodrugs using nanotechnology to improve the efficacy of PDT. The potential limitations and future perspectives of ALA-based nanomedicines are also briefly presented and discussed.

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Inhibition of ABCG2 transporter by lapatinib enhances 5-aminolevulinic acid-mediated protoporphyrin IX fluorescence and photodynamic therapy response in human glioma cell lines

Cited by 25 publications

References 40 publications

The impact of heme biosynthesis regulation on glioma aggressiveness: Correlations with diagnostic molecular markers

The impact of heme biosynthesis regulation on glioma aggressiveness: Correlations with diagnostic molecular markers

5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy

Amplifying the efficacy of ALA-based prodrugs for photodynamic therapy using nanotechnology

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