5-Aminolevulinic Acid Protects against Cisplatin-Induced Nephrotoxicity without Compromising the Anticancer Efficiency of Cisplatin in Rats In Vitro and In Vivo

Terada, Yoshio; Inoue, Keiji; Matsumoto, Tatsuki; Imamura, Masayuki; Hamada, Kazu; Shimamura, Yuto; Ogata, Koji; Inoue, Kosuke; Taniguchi, Yoshinori; Horino, Taro; Karashima, Takashi; Takagi, Kenji; Fukuhara, Hideo; Fujimoto, Shimpei; Tsuda, Masayuki; Shuin, Taro

doi:10.1371/journal.pone.0080850

Cited by 37 publications

(44 citation statements)

References 31 publications

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“…Hou et al reported that ALA had a renoprotective effect in an IRI model via upregulation of HO‐1 and suppressing expression of TNFα and macrophage infiltration . Terada et al reported that ALA upregulated HO‐1 and suppressed tubule cell apoptosis in cisplatin nephropathy . However, in our experiment, the specific HO‐1 inhibitor, ZnPPIX, did not overcome the renoprotective effect of ALA against rhabdomyolysis‐induced AKI.…”

Section: Discussioncontrasting

confidence: 73%

5‐Aminolevulinic acid exerts renoprotective effect via Nrf2 activation in murine rhabdomyolysis‐induced acute kidney injury

et al. 2018

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Section: Discussioncontrasting

confidence: 73%

5‐Aminolevulinic acid exerts renoprotective effect via Nrf2 activation in murine rhabdomyolysis‐induced acute kidney injury

et al. 2018

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“…In fact, the upregulation of HO‐1 has been shown to improve glucose metabolism, and enhance insulin signalling in several animal models of diabetes, which in turn was linked to antioxidant mechanisms . 5‐ALA/SFC produced by haem induces carbon monoxide in mouse kidney by activating HO‐1, demonstrating that 5‐ALA/SFC induces HO‐1 activity. Our findings also showed that 5‐ALA/SFC upregulates HO‐1 expression in the scl‐GvHD mouse model in line with previous reports.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, 5‐ALA is known to induce haem oxygenase‐1 (HO‐1) in vitro and in vivo . HO‐1 acts in haem metabolism as a rate‐limiting enzyme, and the increase in HO‐1 expression generates bilirubin and carbon monoxide, which were shown to act as cytoprotective factors …”

Section: Introductionmentioning

confidence: 99%

Combination of 5‐aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft‐versus‐host disease

Liu

Yang

Zhu

et al. 2018

Experimental Dermatology

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Scleroderma or systemic sclerosis (SSc) is a clinically heterogeneous rheumatological autoimmune disease affecting the skin, internal organs and blood vessels. There is at present no effective treatment for this condition. Our study investigated the effects of 5-aminolevulinic acid (5-ALA), which is a precursor of haem synthesis, on graft-vs-host disease (GvHD)-induced SSc murine model. Lymphocytes were intravenously injected from donor mice (B10.D2) into recipient BALB/c mice (recombination-activating gene 2 (Rag-2)-null mice) deficient in mature T and B cells to induce sclerodermatous GvHD (scl-GvHD). To investigate the effect of 5-ALA on scl-GvHD, combination of 5-ALA and sodium ferrous citrate (SFC) was orally administered to the recipient mice for 9 weeks. 5-ALA/SFC treatment significantly reduced progressive inflammation and fibrosis in the skin and ears. Furthermore, 5-ALA/SFC suppressed mRNA expression of transforming growth factor-β, type I collagen and inflammatory cytokines. These results indicate that the 5-ALA/SFC combination treatment has a protective effect against tissue fibrosis and inflammation in a murine scl-GvHD-induced skin and ear inflammation and fibrosis. Furthermore, the efficacy of 5-ALA/SFC suggests important implications of HO-1 protective activity in autoimmune diseases, and therefore, 5-ALA/SFC may have promising clinical applications. These findings suggested that the 5-ALA/SFC treatment may be the potential strategies for SSc.

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“…5‐aminolevulinic acid (ALA) is widely used to induce protoporphyrin IX (PPIX), a photosensitizer used in photodynamic diagnosis and therapy for non‐muscle invasive bladder cancer . ALA is distributed ubiquitously in mammalian cells and is a precursor of tetrapyrole compounds such as heme, which is essential in aerobic energy metabolism and the electron transport system . ALA reportedly exerts a broad range of cytoprotective effects against cisplatin‐induced nephrotoxicity, rhabdomyolysis‐induced acute kidney injury, hypoxia‐induced cardiomyocyte injury, and low phosphorus loading‐induced neurotoxicity through its antioxidant abilities .…”

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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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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5-Aminolevulinic Acid Protects against Cisplatin-Induced Nephrotoxicity without Compromising the Anticancer Efficiency of Cisplatin in Rats In Vitro and In Vivo

Cited by 37 publications

References 31 publications

5‐Aminolevulinic acid exerts renoprotective effect via Nrf2 activation in murine rhabdomyolysis‐induced acute kidney injury

5‐Aminolevulinic acid exerts renoprotective effect via Nrf2 activation in murine rhabdomyolysis‐induced acute kidney injury

Combination of 5‐aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft‐versus‐host disease

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

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