eEF1A1 binds and enriches protoporphyrin IX in cancer cells in 5-aminolevulinic acid based photodynamic therapy

AbstractPhotodynamic therapy (PDT) is an oxygen-dependent, light-activated, and locally destructive drug treatment of cancer. Protoporphyrin IX (PpIX)-induced PDT exploits cancer cells’ own innate heme biosynthesis to hyper-accumulate the naturally fluorescent and photoactive precursor to heme, PpIX. This occurs as a result of administering heme precursors (e.g., aminolevulinic acid; ALA) because the final step of the pathway (the insertion of ferrous iron into PpIX by ferrochelatase to form heme) is relatively slow. Separate administration of an iron chelating agent has previously been demonstrated to significantly improve dermatological PpIX-PDT by further limiting heme production. A newly synthesized combinational iron chelating PpIX prodrug (AP2-18) has been assessed experimentally in cultured primary human cells of bladder and dermatological origin, as an alternative photosensitizing agent to ALA or its methyl or hexyl esters (MAL and HAL respectively) for photodetection/PDT. Findings indicated that the technique of iron chelation (either through the separate administration of the established hydroxypyridinone iron chelator CP94 or the just as effective combined AP2-18) did not enhance either PpIX fluorescence or PDT-induced (neutral red assessed) cell death in human primary normal and malignant bladder cells. However, 500 µM AP2-18 significantly increased PpIX accumulation and produced a trend of increased cell death within epithelial squamous carcinoma cells. PpIX accumulation destabilized the actin cytoskeleton in bladder cancer cells prior to PDT and resulted in caspase-3 cleavage/early apoptosis afterwards. AP2-18 iron chelation should continue to be investigated for the enhancement of dermatological PpIX-PDT applications but not bladder photodetection/PDT.

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Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells

10.1101/357293 ◽

2018 ◽

Cited By ~ 1

Author(s):

Alicja Sznarkowska ◽

Anna Kostecka ◽

Anna Kawiak ◽

Pilar Acedo ◽

Mattia Lion ◽

...

Keyword(s):

Photodynamic Therapy ◽

Clinical Practice ◽

Tumor Suppressor ◽

Cancer Cells ◽

Ubiquitin Ligase ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Drug Repurposing ◽

Functional Similarity ◽

Photodynamic Therapy Of Cancer

AbstractBackgroundThe p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated ΔN isoform that inhibits TAp73 and p53 and thus, acts as an oncogene.ResultsBy employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid (ALA) applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch.ConclusionOur findings may in future contribute to the successful repurposing of PpIX into clinical practice.

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Enhanced lipid metabolism induces the sensitivity of dormant cancer cells to 5-aminolevulinic acid-based photodynamic therapy

Scientific Reports ◽

10.1038/s41598-021-86886-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Taku Nakayama ◽

Tomonori Sano ◽

Yoshiki Oshimo ◽

Chiaki Kawada ◽

Moe Kasai ◽

...

Keyword(s):

Photodynamic Therapy ◽

Lipid Metabolism ◽

Cancer Cells ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Dependent Manner ◽

Recurrent Cancer ◽

Porphyrin Metabolism ◽

Triacsin C ◽

A Cell

AbstractCancer can develop into a recurrent metastatic disease with latency periods of years to decades. Dormant cancer cells, which represent a major cause of recurrent cancer, are relatively insensitive to most chemotherapeutic drugs and radiation. We previously demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner. Dormant cancer cells exhibited increased porphyrin metabolism and sensitivity to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). However, the metabolic changes in dormant cancer cells or the factors that enhance porphyrin metabolism have not been fully clarified. In this study, we revealed that lipid metabolism was increased in dormant cancer cells, leading to ALA-PDT sensitivity. We performed microarray analysis in non-dormant and dormant cancer cells and revealed that lipid metabolism was remarkably enhanced in dormant cancer cells. In addition, triacsin C, a potent inhibitor of acyl-CoA synthetases (ACSs), reduced protoporphyrin IX (PpIX) accumulation and decreased ALA-PDT sensitivity. We demonstrated that lipid metabolism including ACS expression was positively associated with PpIX accumulation. This research suggested that the enhancement of lipid metabolism in cancer cells induces PpIX accumulation and ALA-PDT sensitivity.

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Dormant cancer cells accumulate high protoporphyrin IX levels and are sensitive to 5-aminolevulinic acid-based photodynamic therapy

Scientific Reports ◽

10.1038/srep36478 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 22

Author(s):

Taku Nakayama ◽

Shimpei Otsuka ◽

Tatsuya Kobayashi ◽

Hodaka Okajima ◽

Kentaro Matsumoto ◽

...

Keyword(s):

Photodynamic Therapy ◽

Cancer Cells ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix

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Enhanced Lipid Metabolism Induces the Sensitivity of Dormant Cancer Cells to 5-aminolevulinic acid-based Photodynamic Therapy

10.21203/rs.3.rs-128840/v1 ◽

2021 ◽

Author(s):

Taku Nakayama ◽

Tomonori Sano ◽

Yoshiki Oshimo ◽

Chiaki Kawada ◽

Moe Kasai ◽

...

Keyword(s):

Photodynamic Therapy ◽

Lipid Metabolism ◽

Cancer Cells ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Dependent Manner ◽

Recurrent Cancer ◽

Porphyrin Metabolism ◽

Triacsin C ◽

A Cell

Abstract Cancer can develop into a recurrent metastatic disease with latency periods of years to decades. Dormant cancer cells, which represent a major cause of recurrent cancer, are relatively insensitive to most chemotherapeutic drugs and radiation. We previously demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner. Dormant cancer cells exhibited increased porphyrin metabolism and sensitivity to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). However, the metabolic changes in dormant cancer cells or the factors that enhance porphyrin metabolism have not been fully clarified. In this study, we revealed that lipid metabolism was increased in dormant cancer cells, leading to ALA-PDT sensitivity. We performed microarray analysis in non-dormant and dormant cancer cells and revealed that lipid metabolism was remarkably enhanced in dormant cancer cells. In addition, triacsin C, a potent inhibitor of acyl-CoA synthetases (ACSs), reduced protoporphyrin IX (PpIX) accumulation and decreased ALA-PDT sensitivity. We demonstrated that lipid metabolism including ACS expression was positively associated with PpIX accumulation. This research suggested that the enhancement of lipid metabolism in cancer cells induces PpIX accumulation and ALA-PDT sensitivity.

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Targeted Photodynamic Therapy Using Alloyed Nanoparticle-Conjugated 5-Aminolevulinic Acid for Breast Cancer

Pharmaceutics ◽

10.3390/pharmaceutics13091375 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1375

Author(s):

Hanieh Montaseri ◽

Cherie Ann Kruger ◽

Heidi Abrahamse

Keyword(s):

Breast Cancer ◽

Photodynamic Therapy ◽

Cancer Cells ◽

Electrostatic Interactions ◽

Breast Cancer Cells ◽

Bimetallic Nanoparticles ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Mcf 7

Photodynamic therapy (PDT) has been investigated as an effective, non-invasive, and alternative tumor-ablative therapy that uses photosensitizers (PSs) and safe irradiation light in the presence of oxygen to generate reactive oxygen species (ROS) to kill malignant cancer cells. However, the off-target activation of the PSs can hinder effective PDT. Therefore, an advanced drug delivery system is required to selectively deliver the PS to the therapeutic region only and reduce off-target side effects in cancer treatment. The integration of laser-initiated PDT with nanotechnology has provided new opportunities in cancer therapy. In this study, plasmonic bimetallic nanoparticles (NPs) were prepared for the targeted PDT (TPDT) of in vitro cultured MCF-7 breast cancer cells. The NPs were functionalized with PEG through Au–thiol linkage to enhance their biocompatibility and subsequently attached to the PS precursor 5-aminolevulinic acid via electrostatic interactions. In order to enhance specific targeting, anti-HER-2 antibodies (Ab) were decorated onto the surface of the nanoconjugate (NC) to fabricate a 5-ALA/Au–Ag-PEG-Ab NC. In vitro studies showed that the synthesized NC can enter MCF-7 cells and localize in the cytoplasm to metabolize 5-ALA to protoporphyrin IX (PpIX). Upon light irradiation, PpIX can efficiently produce ROS for the PDT treatment of MCF-7. Cellular viability studies showed a decrease from 49.8% ± 5.6 ** to 13.8% ± 2.0 *** for free 5-ALA versus the NC, respectively, under equivalent concentrations of the PS (0.5 mM, IC50). These results suggest that the active targeted NC platform has an improved PDT effect on MCF-7 breast cancer cells.

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