5-Aminolevulinic acid-induced protoporphyrin IX with multi-dose ionizing irradiation enhances host antitumor response and strongly inhibits tumor growth in experimental glioma in vivo

Yamamoto, Junkoh; Ogura, Shun‐ichiro; Shimajiri, Shohei; Nakano, Yoshiteru; Akiba, Daisuke; Kitagawa, Takehiro; Ueta, Kunihiro; Tanaka, Tohru; Nishizawa, Shigeru

doi:10.3892/mmr.2014.2991

Cited by 33 publications

(49 citation statements)

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“…Several pharmacological strategies have been exploited to develop effective and minimally‐toxic radiosensitizers including small molecules, macromolecules, and nanomaterials . Preclinical studies demonstrated that ALA administration sensitized glioma, melanoma, and colon adenocarcinoma cells to RT through the generation of PPIX and enhanced ROS that have physico‐chemical interactions with the X‐rays being irradiated into malignant cells . To our knowledge, the present study is the first to confirm that adding in vitro single or in vivo repeated administration of exogenous ALA can act as a radio‐sensitizer for prostate adenocarcinoma cells.…”

Section: Discussionsupporting

confidence: 61%

“…Herein, we investigated the potential use of ALA as a novel radioprotective drug for normal rectal and bladder mucosa. Since RT exerts its biological efficacy partly via an immune response, in vivo research into RT‐induced side effects and cancer radioresistance requires the use of a syngenic model with fully competent immunity . We used a syngenic PCa model of transplantable MyC‐CaP cells in FVB mice to determine whether supplementary oral ALA prevents histopathological damage in mucosal cells without compromising the anticancer effect of RT.…”

Section: Introductionmentioning

confidence: 99%

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Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

et al. 2018

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Background Normal tissue damage caused by radiotherapy remains the largest dose‐limiting factor in radiotherapy for cancer. Therefore, the aim of this study was to investigate the supplementary oral 5‐aminolevulinic acid (ALA) to standard radiation therapy as a novel radioprotective approach that would not compromise the antitumor effect of radiation in normal rectal and bladder mucosa in a syngenic prostate cancer (PCa) model. Methods To evaluate the radiosensitizing effect of ALA in vitro, clonogenic survival assays were performed in DU145, PC3, and MyC‐CaP cell lines. To evaluate the effect of ALA in vivo a single dose (25 Gy) of radiation with or without ALA was given to healthy mice. Next, a syngenic PCa model of MyC‐CaP cells in FVB mice was created, and multiple doses (12 Gy total) of radiation were administered to the mouse pelvic area with or without ALA administration. Resected tumors, recta, and urinary bladders were immunostained with antibodies against Ki‐67, γ‐H2AX, CD204, and uroplakin‐III. Total RNA levels in recta and urinary bladders were analyzed via RT2 Profiler polymerase chain reaction (PCR) arrays related to “Stress & Toxicity PathwayFinder,” “Mitochondria,” and “Inflammasomes.” Results The addition of in vitro single or in vivo repeated administration of exogenous ALA acted as a radiosensitizer for PCa cells. Rectal toxicity was characterized by histological changes including loss of surface epithelium, fibrosis, severe DNA damage, and the aggregation of M2 macrophages. Urinary bladder toxicity was characterized by bladder wall thickening and urothelium denuding. The higher dose (300 mg/kg/day) of ALA exerted a better radioprotective profile than the lower dose (30 mg/kg/day) in normal recta and urinary bladders. Out of the 252 genes tested, 35 (13.4%) were detected as relevant genes which may be involved in the radioprotective role of ALA administration. These included interleukin‐1a (IL‐1a), IL‐1b, IL‐12, chemokine (C‐X‐C motif) ligand 1 (CXCL1), CXCL3, and NLRP3. Conclusions Our study provides novel and comprehensive insights into the dual benefits including radiosensitizing PCa tumor tissues and radioprotection of normal pelvic organs from radiation therapy. Knowledge of the underlying mechanism will facilitate the search for optimal treatment parameters for supplemental oral ALA during radiotherapy for PCa.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

et al. 2018

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“…Previously, we demonstrated that multi-dose ionizing irradiation with repetitive administration of 5-ALA enhanced the radiosensitizing effect in glioma cells in vitro and in vivo, and that intracellular 5-ALA-induced PpIX increased intracellular levels of ROS generated by ionizing irradiation in glioma cells (18,19). before the present study, there had been only one report focusing on the synthesis of 5-ALA-induced PpIX in tumor cells after ionizing irradiation in vitro (17).…”

Section: Discussionmentioning

confidence: 98%

“…These porphyrin compounds of HpD and photofrin have been shown to act as radiosensitizers, yet the radiosensitizing effect of 5-ALA is controversial (15)(16)(17). Previously, we showed that the radiosensitizing effect of 5-ALA via single-dose ionizing irradiation is weak, yet multi-dose ionizing radiation can enhance host antitumor response and strongly inhibit tumor growth in experimental gliomas in vivo (18,19). The mechanism of the radiosensitizing effect of 5-ALA is not clear.…”

Section: -Aminolevulinic Acid Strongly Enhances Delayed Intracellulamentioning

confidence: 99%

“…Moreover, recent studies have reported that 5-ALA can improve the function of the mitochondrial respiratory chain (particularly COX activity) and thereby disrupt the warburg effect and induce caspase-dependent apoptosis in tumor cells (27,28). In our previous study, we demonstrated that multi-dose ionizing radiation induced strong aggregation of activated macrophages with phagocytic features within tumors, causing strong inhibition of tumor growth in glioma cells in vivo (19). Actually, real-time measurement of intracellular ROS is also technically difficult during exposure to ionizing irradiation.…”

Section: -Ala Acts As a Radiosensitizer Via The Enhancement Of Delaymentioning

confidence: 99%

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5-Aminolevulinic acid strongly enhances delayed intracellular production of reactive oxygen species (ROS) generated by ionizing irradiation: Quantitative analyses and visualization of intracellular ROS production in glioma cells in vitro

et al. 2014

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Abstract. Postoperative adjuvant radiotherapy has important roles in multimodal treatment for highly aggressive malignant gliomas. Previously, we demonstrated that multi-dose ionizing irradiation with repetitive administration of 5-aminolevulinic acid (5-ALA) enhanced the host antitumor response and strongly inhibited tumor growth in experimental glioma. However, the mechanism of the radiosensitizing effect of 5-ALA is not known. Ionizing irradiation not only causes reactive oxygen species (ROS) formation initially by water radiolysis but also induces delayed production of mitochondrial ROS for mediating the long-lasting effects of ionizing irradiation on tumor cells. 5-ALA leads to high accumulation of protoporphyrin IX (PpIX) in the mitochondria of tumor cells, yet can also improve dysfunction of the mitochondrial respiratory chain in tumor cells. Here, we assessed the effect of 5-ALA-induced PpIX synthesis and delayed production of intracellular ROS after ionizing irradiation with 5-ALA in glioma cells in vitro. Temporal changes in intracellular 5-ALA-induced PpIX synthesis after ionizing irradiation in glioma cell lines were evaluated using flow cytometry (FCM). Then, the effect of 5-ALA on delayed production of intracellular ROS 12 h after ionizing irradiation in glioma cells was evaluated by FCM and confocal laser scanning microscopy. Ionizing irradiation had no effect on 5-ALA-induced PpIX synthesis in glioma cells. Delayed intracellular production of ROS was significantly higher than that just after ionizing irradiation, but 5-ALA pretreatment strongly enhanced the delayed intracellular production of ROS, mainly in the cytoplasm of glioma cells. This 5-ALA-induced increase in the delayed production of ROS tended to be higher in the case of 5-ALA treatment before rather than after ionizing irradiation. These results suggest that 5-ALA can affect tumor cells under ionizing irradiation, and greatly increase secondary intracellular production of ROS long after ionizing irradiation, thereby causing a radiosensitizing effect in glioma cells.

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The use of radiosensitizing agents in the therapy of glioblastoma multiforme—a comprehensive review

2022

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Background Glioblastoma is the most common malignant brain tumor in human adults. Despite several improvements in resective as well as adjuvant therapy over the last decades, its overall prognosis remains poor. As a means of improving patient outcome, the possibility of enhancing radiation response by using radiosensitizing agents has been tested in an array of studies. Methods A comprehensive review of clinical trials involving radiation therapy in combination with radiosensitizing agents on patients diagnosed with glioblastoma was performed in the National Center for Biotechnology Information’s PubMed database. Results A total of 96 papers addressing this matter were published between 1976 and 2021, of which 63 matched the subject of this paper. All papers were reviewed, and their findings discussed in the context of their underlining mechanisms of radiosensitization. Conclusion In the history of glioblastoma treatment, several approaches of optimizing radiation-effectiveness using radiosensitizers have been made. Even though several different strategies and agents have been explored, clear evidence of improved patient outcome is still missing. Tissue-selectiveness and penetration of the blood–brain barrier seem to be major roadblocks; nevertheless, modern strategies try to circumvent these obstacles, using novel sensitizers based on preclinical data or alternative ways of delivery.

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5-Aminolevulinic acid-induced protoporphyrin IX with multi-dose ionizing irradiation enhances host antitumor response and strongly inhibits tumor growth in experimental glioma in vivo

Cited by 33 publications

References 37 publications

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

5-Aminolevulinic acid strongly enhances delayed intracellular production of reactive oxygen species (ROS) generated by ionizing irradiation: Quantitative analyses and visualization of intracellular ROS production in glioma cells in vitro

The use of radiosensitizing agents in the therapy of glioblastoma multiforme—a comprehensive review

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