Mechanism of cell death by 5‐aminolevulinic acid‐based photodynamic action and its enhancement by ferrochelatase inhibitors in human histiocytic lymphoma cell line U937

Amo, Takashi; Kawanishi, Noriaki; Uchida, Masataka; Fujita, Hirofumi; Oyanagi, Eri; Utsumi, Toshihiko; Ogino, Tetsuya; Inoue, Keiji; Shuin, Taro; Utsumi, Kozo; Sasaki, Junzo

doi:10.1002/cbf.1603

Cited by 49 publications

(42 citation statements)

References 59 publications

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“…Research show that PDT might act on hyperproliferating cells, which selectively uptake ALA and undergo apoptosis and necrosis following PDT. 29 It also has been suggested that PDT may have immunomodulatory e®ect based on the fact that there is an increase in the CD8þ reaction in the damaged tissue following PDT. The initial pain and soreness indicate that there may be an in°ux of new T cells, followed by an overall reduction in the number of in°ammatory cells and tissue healing.…”

Section: Discussionmentioning

confidence: 99%

Treatment of cutaneous lichen planus with ALA-mediated topical photodynamic therapy

Fan

Zhang

Wang

et al. 2015

J. Innov. Opt. Health Sci.

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Purpose: To evaluate the e®ectiveness of topical 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) for the treatment of cutaneous lichen planus (LP). Methods: A total of 17 symptomatic LP lesions in 7 Chinese patients were assessed. ALA cream (10%) was applied topically to LP lesions for 3 h. The lesions were irradiated with a 635 nm diode laser at the dose level of 100 J/cm 2 . The treatment was repeated at two-week intervals. Clinical assessment was conducted before each treatment. Follow-up was performed once a month for up to six months. Results: Lesions showed signi¯cant improvement after one to four courses of treatments. Complete response was achieved in 13 lesions (¯ve patients) and partial remission in four lesions (two patients). The complete response rate was 71%. There was no signi¯cant side e®ects except the feeling of pain that most patients could tolerate. Follow-up of¯ve patients who achieved complete response showed no signs of recurrence. Conclusion: Topical ALA PDT is e®ective in the treatment of cutaneous LP.

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Section: Discussionmentioning

confidence: 99%

Treatment of cutaneous lichen planus with ALA-mediated topical photodynamic therapy

Fan

Zhang

Wang

et al. 2015

J. Innov. Opt. Health Sci.

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“…An increase in erythrocyte zinc PPIX is an early indicator of iron deficiency and precedes the development of anemia (Labbe et al, 1999). Iron chelators can bind to ferrous iron in the cytoplasm of cells, such as hepatocytes, and prevent iron from entering mitochondria to reduce FECH function and cause PPIX accumulation (Amo et al, 2009;Blake and Curnow, 2010;Juzeniene et al, 2013). In rodent and chick embryo livers and isolated hepatocytes, iron chelation can limit heme synthesis sufficiently to potentiate induction of ALAS1 by drugs and steroids (Anderson et al, 1982).…”

Section: Disregulation Of Ppix Homeostasismentioning

confidence: 99%

Protoporphyrin IX: the Good, the Bad, and the Ugly

Sachar

Anderson

2015

Journal of Pharmacology and Experimental Therapeutics

189

159

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Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects.

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“…Although 5-ALA-PDT has been intensively studied for several decades, the mechanism underlying its cytotoxicity is not well known. It has been demonstrated that 5-ALA-PDT leads to apoptosis when PpIX accumulates in the mitochondria and to necrosis when it diffuses into the cytoplasm (7). A previous study reported that 5-ALA-PDT induced autophagic cell death through the activation of adenosine monophosphate-activated protein kinase (AMPK) (8).…”

Section: Introductionmentioning

confidence: 99%

Metformin enhances the cytotoxicity of 5-aminolevulinic acid-mediated photodynamic therapy in vitro

et al. 2017

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Abstract.The biguanide metformin is a drug widely used for the treatment of type 2 diabetes. Metformin enhances the cytotoxicity of chemotherapy by promoting the adenosine monophosphate-activated protein kinase (AMPK) autophagy signaling pathway. Photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA), a precursor of protoporphyrin IX (PpIX), leads to apoptosis when PpIX accumulates in the mitochondria, and also leads to autophagy through activation of AMPK. In the present study, the effect of metformin in combination with 5-ALA-PDT was evaluated in vitro in KLN205 lung cancer cells. At a fluence of 5 J/cm 2 , 5-ALA-PDT in combination with 5 mM metformin exhibited significantly increased cytotoxicity compared with that observed with 0 and 0.1 mM metformin (P=0.0197 and P=0.0423, respectively). The cells treated with 5-ALA-PDT and metformin exhibited condensation of nuclear chromatin and the presence of autophagosomes. These results indicate that apoptosis and autophagy occur in KLN205 cells following combined treatment with 5-ALA-PDT and metformin. The results from the present study are the first to indicate, to the best of our knowledge, that metformin potentiates the efficacy of 5-ALA-PDT. IntroductionPhotodynamic therapy (PDT) has been developed as an effective treatment for malignant tumors. PDT involves the administration of a photosensitizer, which preferentially accumulates in malignant tissue, and its subsequent activation by light of the appropriate wavelength (1,2). The interaction of light with the intracellular photosensitizer causes the release of oxygen radicals, leading to cell death (3).5-Aminolevulinic acid (5-ALA) is a precursor of protoporphyrin IX (PpIX), a well-known photosensitizer, and is converted in situ to PpIX via the heme biosynthetic pathway (4). 5-ALA has been used successfully for photodynamic diagnosis and PDT (5,6). Although 5-ALA-PDT has been intensively studied for several decades, the mechanism underlying its cytotoxicity is not well known. It has been demonstrated that 5-ALA-PDT leads to apoptosis when PpIX accumulates in the mitochondria and to necrosis when it diffuses into the cytoplasm (7). A previous study reported that 5-ALA-PDT induced autophagic cell death through the activation of adenosine monophosphate-activated protein kinase (AMPK) (8).The biguanide metformin (N,N-dimethylimidodicarbonimidic diamide), a widely used drug for the treatment of type 2 diabetes, reduces blood glucose levels by suppressing gluconeogenesis in the liver and increasing glucose uptake by the skeletal muscle (9,10). Additionally, metformin has been demonstrated to significantly inhibit tumor growth in several types of cancer and mouse tumor models (11-13). It was reported that metformin can control the proliferation of cancer cells, and this effect was associated with a number of signaling pathways, including the activation of AMPK and mitogen-activated protein kinase (MAPK) signaling, and decreased mammalian target of rapamycin (mTOR) and epidermal growth factor signaling (14).Severa...

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Mechanism of cell death by 5‐aminolevulinic acid‐based photodynamic action and its enhancement by ferrochelatase inhibitors in human histiocytic lymphoma cell line U937

Cited by 49 publications

References 59 publications

Treatment of cutaneous lichen planus with ALA-mediated topical photodynamic therapy

Treatment of cutaneous lichen planus with ALA-mediated topical photodynamic therapy

Protoporphyrin IX: the Good, the Bad, and the Ugly

Metformin enhances the cytotoxicity of 5-aminolevulinic acid-mediated photodynamic therapy in vitro

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