scholarly journals 5-aminolaevulinic acid (5-ALA) accumulates in GIST-T1 cells and photodynamic diagnosis using 5-ALA identifies gastrointestinal stromal tumors (GISTs) in xenograft tumor models

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249650
Author(s):  
Makiko Sasaki ◽  
Mamoru Tanaka ◽  
Hiroshi Ichikawa ◽  
Taketo Suzuki ◽  
Hirotada Nishie ◽  
...  
Keyword(s):  
Aminolevulinic Acid ◽  
Protoporphyrin Ix ◽  
Fluorescence Emission ◽  
Immunofluorescent Staining ◽  
Photodynamic Diagnosis ◽  
Submucosal Tumors ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Preferential Uptake ◽  
Clinical Potential

Gastrointestinal stromal tumor (GIST) diagnosis using conventional gastrointestinal endoscopy is difficult because such malignancies cannot be distinguished from other types of submucosal tumors. Photodynamic diagnosis (PDD) is based on the preferential uptake of photosensitizers by tumor tissues and its detection by fluorescence emission upon laser excitation. In this study, we investigated whether PDD using 5-aminolevulinic acid (5-ALA), a standard photosensitizer used worldwide, could be used for GIST diagnosis. 5-ALA is metabolized to endogenous fluorescent protoporphyrin IX (PpIX). We examined the accumulation of PpIX in GIST-T1 cells using flow cytometry and immunofluorescent staining. Furthermore, we established GIST-T1 xenograft mouse models and examined PpIX accumulation in the resultant tumors. PpIX accumulated in GIST-T1 cells and was localized mainly to lysosomes. PpIX accumulation was also observed in murine xenograft tumors. Moreover, tumor and normal tissues could be distinctly identified by relative PpIX fluorescence. Thus, our results demonstrated that PDD with 5-ALA has substantial clinical potential for GIST diagnosis.

scholarly journals Systematic Review and Meta-Analysis of In Vitro Anti-Human Cancer Experiments Investigating the Use of 5-Aminolevulinic Acid (5-ALA) for Photodynamic Therapy

2021 ◽  
Vol 14 (3) ◽  
pp. 229
Author(s):  
Yo Shinoda ◽  
Daitetsu Kato ◽  
Ryosuke Ando ◽  
Hikaru Endo ◽  
Tsutomu Takahashi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Photodynamic Therapy ◽  
Aminolevulinic Acid ◽  
Human Cancer ◽  
Meta Analysis ◽  
Protoporphyrin Ix ◽  
Cell Types ◽  
Amino Acid Derivative ◽  
Photodynamic Diagnosis

5-Aminolevulinic acid (5-ALA) is an amino acid derivative and a precursor of protoporphyrin IX (PpIX). The photophysical feature of PpIX is clinically used in photodynamic diagnosis (PDD) and photodynamic therapy (PDT). These clinical applications are potentially based on in vitro cell culture experiments. Thus, conducting a systematic review and meta-analysis of in vitro 5-ALA PDT experiments is meaningful and may provide opportunities to consider future perspectives in this field. We conducted a systematic literature search in PubMed to summarize the in vitro 5-ALA PDT experiments and calculated the effectiveness of 5-ALA PDT for several cancer cell types. In total, 412 articles were identified, and 77 were extracted based on our inclusion criteria. The calculated effectiveness of 5-ALA PDT was statistically analyzed, which revealed a tendency of cancer-classification-dependent sensitivity to 5-ALA PDT, and stomach cancer was significantly more sensitive to 5-ALA PDT compared with cancers of different origins. Based on our analysis, we suggest a standardized in vitro experimental protocol for 5-ALA PDT.

scholarly journals Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Sadahiro Kaneko ◽  
Sadao Kaneko
Keyword(s):  
Malignant Glioma ◽  
Anticancer Agents ◽  
Aminolevulinic Acid ◽  
Malignant Gliomas ◽  
Protoporphyrin Ix ◽  
Time Spectrum ◽  
Photodynamic Diagnosis ◽  
Promising Technique ◽  
New Methods ◽  
New Treatments

Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD.

Fluorescent analysis of 5-aminolevulinic acid-induced protoporphyrin-IX in mouse transplanted tumor tissues

2003 ◽  
Vol 1248 ◽  
pp. 405-408 ◽  
Author(s):  
Toshiyuki Ogasawara ◽  
Norio Miyoshi ◽  
Masaru Fukuda ◽  
Tetsushi Yamada ◽  
Toru Ogawa ◽  
...  
Keyword(s):  
Aminolevulinic Acid ◽  
Protoporphyrin Ix ◽  
Fluorescent Analysis ◽  
Transplanted Tumor ◽  
Tumor Tissues

scholarly journals The use of 5-aminolevulinic acid and its derivatives in photodynamic therapy and diagnosis

2018 ◽  
Vol 67 (4) ◽  
pp. 113-130
Author(s):  
Anna Romiszewska ◽  
Aneta Bombalska
Keyword(s):  
Photodynamic Therapy ◽  
Aminolevulinic Acid ◽  
Protoporphyrin Ix ◽  
Photodynamic Diagnosis ◽  
Chemical Derivatives ◽  
Therapeutic Outcomes ◽  
Keywords Photodynamic Therapy ◽  
Therapy And Diagnosis ◽  
Derivatives Of ◽  
Ala Esters

5-aminolevulinic acid (5-ALA) is used as a drug in the photodynamic therapy (PDT) and photodynamic diagnosis (PDD) of cancer. Combined with irradiation at the appropriate wavelength, it is used as a photosensitizer precursor to identify/kill tumour cells. In cells, 5-aminolevulinic acid is converted to protoporphyrin IX (PpIX), which is the precursor of hemin. Internal application of 5-ALA induces the overproduction of the endogenous photosensitizer, PpIX, which can subsequently be activated by light at the appropriate wavelength. 5-ALA can be applied internally to trans-mutated areas or be injected directly into them. Chemical derivatives of 5ALA have the potential to improve bioavailability, enhance stability and lead to better therapeutic outcomes for treated patients. 5-ALA is currently the most commonly used drug in the photodynamic therapy and diagnosis (PDT/PDD) of cancers. Keywords: photodynamic therapy, photodynamic diagnosis, 5-aminolevulinic acid (5- ALA), esters of 5-aminolevulinic acid, cancer.

scholarly journals MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

2020 ◽  
Author(s):  
Vipin Shankar Chelakkot ◽  
Kaiwen Liu ◽  
Ema Yoshioka ◽  
Shaykat Saha ◽  
Danyang Xu ◽  
...  
Keyword(s):  
Aminolevulinic Acid ◽  
Human Cancer ◽  
Protoporphyrin Ix ◽  
Mek Inhibitor ◽  
Photodynamic Diagnosis ◽  
Human Cancer Cell ◽  
Nih3t3 Cells ◽  
Human Cancer Cell Lines ◽  
Oncogenic Ras ◽  
Specific Accumulation

AbstractThe efficacy of aminolevulinic acid (5-ALA)-based photodynamic diagnosis (5-ALA-PDD) and photodynamic therapy (5-ALA-PDT) is dependent on the 5-ALA-induced cancer-specific accumulation of protoporphyrin IX (PpIX). We previously reported that inhibition of oncogenic Ras/MEK increases PpIX accumulation in cancer cells by reducing PpIX efflux through ATP-binding cassette sub-family B member 1 (ABCB1) as well as PpIX conversion to heme by ferrochelatase (FECH). Here, we sought to identify the downstream pathways of Ras/MEK involved in the regulation of PpIX accumulation via ABCB1 and FECH. First, we demonstrated that Ras/MEK activation reduced PpIX accumulation in RasV12-transformed NIH3T3 cells and HRAS transgenic mice. Knockdown of p90 ribosomal S6 kinases (RSK) 2, 3, or 4 increased PpIX accumulation in the RasV12-transformed NIH3T3 cells. Further, treatment with an RSK inhibitor reduced ABCB1 expression and increased PpIX accumulation. Moreover, HIF-1α expression was reduced when the RasV12-transformed NIH3T3 cells were treated with a MEK inhibitor, demonstrating that HIF-1α is a downstream element of MEK. HIF-1α inhibition decreased the activity of FECH and increased PpIX accumulation. Finally, we demonstrated the involvement of RSKs and HIF-1α in the regulation of PpIX accumulation in human cancer cell lines (DLD-1, SNB-75, Hs 578T, and MDA MB 231). These results demonstrate that the RSK-ABCB1 and HIF-1α-FECH axes are the downstream pathways of Ras/MEK involved in the regulation of PpIX accumulation.

scholarly journals MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vipin Shankar Chelakkot ◽  
Kaiwen Liu ◽  
Ema Yoshioka ◽  
Shaykat Saha ◽  
Danyang Xu ◽  
...  
Keyword(s):  
Aminolevulinic Acid ◽  
Human Cancer ◽  
Protoporphyrin Ix ◽  
Mek Inhibitor ◽  
Photodynamic Diagnosis ◽  
Human Cancer Cell ◽  
Nih3t3 Cells ◽  
Human Cancer Cell Lines ◽  
Oncogenic Ras ◽  
Specific Accumulation

AbstractThe efficacy of aminolevulinic acid (5-ALA)-based photodynamic diagnosis (5-ALA-PDD) and photodynamic therapy (5-ALA-PDT) is dependent on 5-ALA-induced cancer-specific accumulation of protoporphyrin IX (PpIX). We previously reported that inhibition of oncogenic Ras/MEK increases PpIX accumulation in cancer cells by reducing PpIX efflux through ATP-binding cassette sub-family B member 1 (ABCB1) and ferrochelatase (FECH)-catalysed PpIX conversion to haem. Here, we sought to identify the downstream pathways of Ras/MEK involved in the regulation of PpIX accumulation via ABCB1 and FECH. First, we demonstrated that Ras/MEK activation reduced PpIX accumulation in RasV12-transformed NIH3T3 cells and HRAS transgenic mice. Knockdown of p90 ribosomal S6 kinases (RSK) 2, 3, or 4 increased PpIX accumulation in RasV12-transformed NIH3T3 cells. Further, treatment with an RSK inhibitor reduced ABCB1 expression and increased PpIX accumulation. Moreover, HIF-1α expression was reduced when RasV12-transformed NIH3T3 cells were treated with a MEK inhibitor, demonstrating that HIF-1α is a downstream element of MEK. HIF-1α inhibition decreased FECH activity and increased PpIX accumulation. Finally, we demonstrated the involvement of RSKs and HIF-1α in the regulation of PpIX accumulation in human cancer cell lines. These results demonstrate that the RSK-ABCB1 and HIF-1α-FECH axes are the downstream pathways of Ras/MEK involved in the regulation of PpIX accumulation.

scholarly journals Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukaemia cells

2019 ◽  
Author(s):  
Liren Jiang ◽  
Natasha Malik ◽  
Pilar Acedo ◽  
Joanna Zawacka-Pankau
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Lymphocytic Leukaemia ◽  
Aminolevulinic Acid ◽  
Tumor Regression ◽  
Protoporphyrin Ix ◽  
Photodynamic Diagnosis ◽  
Dual Inhibitor ◽  
Normal Cells ◽  
Cell Chronic Lymphocytic Leukaemia

Abstractp53 is a tumor suppressor, which belongs to the p53 family of proteins. The family consists of p53, p63 and p73 proteins, which share similar structure and function. Activation of wild-type p53 or TAp73 in tumors leads to tumor regression, and small molecules restoring the p53 pathway are in clinical development.Protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid, is a clinically approved drug applied in photodynamic diagnosis and therapy. PpIX induces p53- and TAp73-dependent apoptosis and inhibits TAp73/MDM2 and TAp73/MDM4 interactions. Here we demonstrate that PpIX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and activates apoptosis in B-cell chronic lymphocytic leukaemia cells without illumination and without affecting normal cells. PpIX stabilizes p53 and TAp73 proteins, induces p53-downstream apoptotic targets and provokes cancer cell death at doses non-toxic to normal cells.Our findings open up new opportunities for repurposing PpIX for treating lymphoblastic leukaemias withwtTP53.

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