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

Lai, Hung Wei; Nakayama, Taku; Ogura, Shun‐ichiro

doi:10.1007/s10147-020-01766-y

Cited by 13 publications

(3 citation statements)

References 61 publications

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“…After its entry into the cell, ALA is converted into PpIX and heme through a series of enzyme-mediated reactions in the cell [ 22 , 23 ]. The uptake of ALA into the cell can be determined by measuring the concentration of PpIX and heme produced using high performance liquid chromatography (HPLC) as described in the Materials & Methods.…”

Section: Resultsmentioning

confidence: 99%

Suppression of angiotensin converting enzyme 2, a host receptor for SARS-CoV-2 infection, using 5-aminolevulinic acid in vitro

et al. 2023

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Angiotensin converting enzyme 2 (ACE2), an entry receptor found on the surface of host cells, is believed to be detrimental to the infectious capability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Scientists have been working on finding a cure since its outbreak with limited success. In this study, we evaluated the potential of 5-aminolevulinic acid hydrochloride (ALA) in suppressing ACE2 expression of host cells. ACE2 expression and the production of intracellular porphyrins following ALA administration were carried out. We observed the reduction of ACE2 expression and intracellular porphyrins following ALA administration. ALA suppressed the ACE2 expression in host cells which might prevent binding of SARS-CoV-2 to host cells. Co-administration of ALA and sodium ferrous citrate (SFC) resulted in a further decrease in ACE2 expression and increase in intracellular heme level. This suggests that the suppression of ACE2 expression by ALA might occur through heme production. We found that the inhibition of heme oxygenase-1 (HO-1), which is involved in heme degradation, also resulted in decrease in ACE2 expression, suggesting a potential role of HO-1 in suppressing ACE2 as well. In conclusion, we speculate that ALA, together with SFC administration, might serve as a potential therapeutic approach in reducing SARS-CoV-2 infectivity through suppression of ACE2 expression.

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Section: Resultsmentioning

confidence: 99%

Suppression of angiotensin converting enzyme 2, a host receptor for SARS-CoV-2 infection, using 5-aminolevulinic acid in vitro

et al. 2023

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“…Ogura has been exploring the role of transporters involved in the heme metabolism very attentively [ 122 ]. Lately, his group demonstrated the importance of PAT1 and PEPT1 upon 5-ALA administration, depending on the malignancy of the DU145 prostate cancer cell line [ 123 ].…”

Section: Concerning Ppix Selective Accumulation In Neoplastic Cellsmentioning

confidence: 99%

A Recap of Heme Metabolism towards Understanding Protoporphyrin IX Selectivity in Cancer Cells

Kiening

Lange

2022

IJMS

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Mitochondria are essential organelles of mammalian cells, often emphasized for their function in energy production, iron metabolism and apoptosis as well as heme synthesis. The heme is an iron-loaded porphyrin behaving as a prosthetic group by its interactions with a wide variety of proteins. These complexes are termed hemoproteins and are usually vital to the whole cell comportment, such as the proteins hemoglobin, myoglobin or cytochromes, but also enzymes such as catalase and peroxidases. The building block of porphyrins is the 5-aminolevulinic acid, whose exogenous administration is able to stimulate the entire heme biosynthesis route. In neoplastic cells, this methodology repeatedly demonstrated an accumulation of the ultimate heme precursor, the fluorescent protoporphyrin IX photosensitizer, rather than in healthy tissues. While manifold players have been proposed, numerous discrepancies between research studies still dispute the mechanisms underlying this selective phenomenon that yet requires intensive investigations. In particular, we wonder what are the respective involvements of enzymes and transporters in protoporphyrin IX accretion. Is this mainly due to a boost in protoporphyrin IX anabolism along with a drop of its catabolism, or are its transporters deregulated? Additionally, can we truly expect to find a universal model to explain this selectivity? In this report, we aim to provide our peers with an overview of the currently known mitochondrial heme metabolism and approaches that could explain, at least partly, the mechanism of protoporphyrin IX selectivity towards cancer cells.

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“…The 5-ALA excess in the body circumvents the negative feedback regulation in heme biosynthesis and leads to the selective accumulation of PpIX in glioma cells 13 , 14 . The mechanism of this process is not entirely clear 13 , 15 (for recent reviews, see 16 – 18 ). The availability of 5-ALA from blood vessels in the brain is an essential factor 19 – 21 because an intact blood–brain barrier (BBB) is impermeable to 5-ALA 13 .…”

Section: Introductionmentioning

confidence: 99%

Protoporphyrin IX in serum of high-grade glioma patients: A novel target for disease monitoring via liquid biopsy

Walke,

Krone,

Stummer

et al. 2024

Sci Rep

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High-grade gliomas (HGG) carry a dismal prognosis. Diagnosis comprises MRI followed by histopathological evaluation of tissue; no blood biomarker is available. Patients are subjected to serial MRIs and, if unclear, surgery for monitoring of tumor recurrence, which is laborious. MRI provides only limited diagnostic information regarding the differentiation of true tumor progression from therapy-associated side effects. 5-aminolevulinic acid (5-ALA) is routinely used for induction of protoporphyrin IX (PpIX) accumulation in malignant glioma tissue, enabling improved tumor visualization during fluorescence-guided resection (FGR). We investigated whether PpIX can also serve as a serum HGG marker to monitor relapse. Patients (HGG: n = 23 primary, pHGG; n = 5 recurrent, rHGG) undergoing FGR received 5-ALA following standard clinical procedure. The control group of eight healthy volunteers (HCTR) also received 5-ALA. Serum was collected before and repeatedly up to 72 h after drug administration. Significant PpIX accumulation in HGG was observed after 5-ALA administration (ANOVA: p = 0.005, post-hoc: HCTR vs. pHGG p = 0.029, HCTR vs. rHGG p = 0.006). Separation of HCTR from pHGG was possible when maximum serum PpIX levels were reached (CI95% of tMax). ROC analysis of serum PpIX within CI95% of tMax showed successful classification of HCTR and pHGG (AUCROC 0.943, CI95% 0.884–1.000, p < 0.001); the optimal cut-off for diagnosis was 1275 pmol PpIX/ml serum, reaching 87.0% accuracy, 90.5% positive predictive and 84.0% negative predictive value. Baseline PpIX level was similar in patient and control groups. Thus, 5-ALA is required for PpIX induction, which is safe at the standard clinical dosage. PpIX is a new target for liquid biopsy in glioma. More extensive clinical studies are required to characterize its full potential.

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

Cited by 13 publications

References 61 publications

Suppression of angiotensin converting enzyme 2, a host receptor for SARS-CoV-2 infection, using 5-aminolevulinic acid in vitro

Suppression of angiotensin converting enzyme 2, a host receptor for SARS-CoV-2 infection, using 5-aminolevulinic acid in vitro

A Recap of Heme Metabolism towards Understanding Protoporphyrin IX Selectivity in Cancer Cells

Protoporphyrin IX in serum of high-grade glioma patients: A novel target for disease monitoring via liquid biopsy

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