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Mitochondrial Localization of ABC Transporter ABCG2 and Its Function in 5-Aminolevulinic Acid-Mediated Protoporphyrin IX Accumulation  [PDF]
Hirotsugu Kobuchi, Koko Moriya, Tetsuya Ogino, Hirofumi Fujita, Keiji Inoue, Taro Shuin, Tatsuji Yasuda, Kozo Utsumi, Toshihiko Utsumi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050082
Abstract: Accumulation of protoporphyrin IX (PpIX) in malignant cells is the basis of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy. We studied the expression of proteins that possibly affect ALA-mediated PpIX accumulation, namely oligopeptide transporter-1 and -2, ferrochelatase and ATP-binding cassette transporter G2 (ABCG2), in several tumor cell lines. Among these proteins, only ABCG2 correlated negatively with ALA-mediated PpIX accumulation. Both a subcellular fractionation study and confocal laser microscopic analysis revealed that ABCG2 was distributed not only in the plasma membrane but also intracellular organelles, including mitochondria. In addition, mitochondrial ABCG2 regulated the content of ALA-mediated PpIX in mitochondria, and Ko143, a specific inhibitor of ABCG2, enhanced mitochondrial PpIX accumulation. To clarify the possible roles of mitochondrial ABCG2, we characterized stably transfected-HEK (ST-HEK) cells overexpressing ABCG2. In these ST-HEK cells, functionally active ABCG2 was detected in mitochondria, and treatment with Ko143 increased ALA-mediated mitochondrial PpIX accumulation. Moreover, the mitochondria isolated from ST-HEK cells exported doxorubicin probably through ABCG2, because the export of doxorubicin was inhibited by Ko143. The susceptibility of ABCG2 distributed in mitochondria to proteinase K, endoglycosidase H and peptide-N-glycosidase F suggested that ABCG2 in mitochondrial fraction is modified by N-glycans and trafficked through the endoplasmic reticulum and Golgi apparatus and finally localizes within the mitochondria. Thus, it was found that ABCG2 distributed in mitochondria is a functional transporter and that the mitochondrial ABCG2 regulates ALA-mediated PpIX level through PpIX export from mitochondria to the cytosol.
Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer  [PDF]
Ma?gorzata Wachowska,Angelika Muchowicz,Ma?gorzata Firczuk,Magdalena Gabrysiak,Magdalena Winiarska,Ma?gorzata Wańczyk,Kamil Bojarczuk,Jakub Golab
Molecules , 2011, DOI: 10.3390/molecules16054140
Abstract: Aminolevulinic acid (ALA) is an endogenous metabolite normally formed in the mitochondria from succinyl-CoA and glycine. Conjugation of eight ALA molecules yields protoporphyrin IX (PpIX) and finally leads to formation of heme. Conversion of PpIX to its downstream substrates requires the activity of a rate-limiting enzyme ferrochelatase. When ALA is administered externally the abundantly produced PpIX cannot be quickly converted to its final product - heme by ferrochelatase and therefore accumulates within cells. Since PpIX is a potent photosensitizer this metabolic pathway can be exploited in photodynamic therapy (PDT). This is an already approved therapeutic strategy making ALA one of the most successful prodrugs used in cancer treatment.
Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis  [PDF]
Toshihisa Ishikawa,Hiroshi Nakagawa,Yuichiro Hagiya,Naosuke Nonoguchi,Shin-ichi Miyatake,Toshihiko Kuroiwa
Advances in Pharmacological Sciences , 2010, DOI: 10.1155/2010/587306
Abstract: Accumulating evidence indicates that ATP-binding cassette (ABC) transporter ABCG2 plays a key role in regulating the cellular accumulation of porphyrin derivatives in cancer cells and thereby affects the efficacy of photodynamic therapy and photodynamic diagnosis. The activity of porphyrin efflux can be affected by genetic polymorphisms in the ABCG2 gene. On the other hand, Nrf2, an NF-E2-related transcription factor, has been shown to be involved in oxidative stress-mediated induction of the ABCG2 gene. Since patients have demonstrated individual differences in their response to photodynamic therapy, transcriptional activation and/or genetic polymorphisms of the ABCG2 gene in cancer cells may affect patients' responses to photodynamic therapy. Protein kinase inhibitors, including imatinib mesylate and gefitinib, are suggested to potentially enhance the efficacy of photodynamic therapy by blocking ABCG2-mediated porphyrin efflux from cancer cells. This review article provides an overview on the role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis. 1. Introduction Photodynamic therapy (PDT) and photodynamic diagnosis are achieved by a photon-induced physicochemical reaction which is induced by excitation of photosensitizer exposed to light. In the 1960s Lipson and Baldes introduced a hematoporphyrin derivative (HpD), a product derived following by treatment of hematoporphyrin with a mixture of acetic and sulfuric acids and sodium hydroxide [1]. Their development of the hematoporphyrin derivative established the basis of today’s PDT and photodynamic diagnosis [2–6]. PDT utilizes porphyrin derivatives to generate singlet oxygen (1O2) and other reactive oxygen species (ROS) that are potent in killing cancer cell in vivo [7]. The modern era of PDT was founded in the 1970s with the pioneering work of Dougherty and his coworkers who purified HpD later called Photofrin. In 1978, Dougherty et al. had carried out the first human trials of Photofrin on women with advanced breast cancer [8]. Photofrin is still the most widely used photosensitizer in clinical PDT. Recent studies of modern PDT began just two decades ago; therefore there are still unsolved problems. Nevertheless, PDT has many applications in a wide range of fields of both preclinical and clinical sciences. In recent years, remarkable advances were made in photodynamic diagnosis technology that makes it easier to reliably achieve complete excision of malignant gliomas [9–11] and meningiomas [12]. The extent of tumor resection that should be undertaken in patients with
New photosensitizers versus aminolevulinic acid (ala) in experimental photodynamic therapy of actinic keratosis – A case report  [cached]
Bogdan Stanoiu,Eduard Crauciuc,Ovidiu Toma,Rodica-Mariana Ion
Analele ?tiin?ifice Ale Universit??ii Alexandru Ioan Cuza din Ia?i,Sectiunea II A : Genetica si Biologie Moleculara , 2009,
Abstract: Photodynamic therapy (PDT) is increasingly being recognized as an attractive, alternative treatment modality for superficial cancer, being an emerging method for local destruction of tissue by generating toxic oxygen species using light absorbed by an administered or an endogenously generated photosensitizer (porphyrins, phthalocyanines, khellin, hypericin, riboflavin). A considerable number of PDT research over the past ten years has been devoted to the development of new sensitizers. The development of new photosensitizers for localization and treatment of tumors is a research area or current interest. The data show that, when properly used, PDT is an effective alternative treatment option in oncology. This paper will present a case study of actinic keratosis treated with aminolevulinic acid (ALA) and 5, 10, 15, 20 - tetra (4-sulfophenyl) porphyrin (TSPP) in a photodynamic therapy approach. The clinical data proved the efficacy and safety of the method and the new drug. From skin biopsies we have obtained lower absolute number of keratinocytes compared to control skin. The in vitro tests showed cells having lower viability, lower proliferation capacity, and high apoptosis/necrosis percentages; therefore after applying PDT we have obtained an active destruction of the cells
Photodynamic Therapy with 5-Aminolevulinic acid (ALA) Impairs Tumor Initiating and Chemo-Resistance Property in Head and Neck Cancer-Derived Cancer Stem Cells  [PDF]
Chuan-Hang Yu, Cheng-Chia Yu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087129
Abstract: Background Head and neck cancer (HNC) ranks the fourth leading malignancy and cancer death in male population in Taiwan. Despite recent therapeutic advances, the prognosis for HNC patients is still dismal. New strategies are urgently needed to improve the chemosensitization to conventional chemotherapeutic drugs and clinical responses of HNC patients. Studies have demonstrated that topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is being used in the treatment of various human premalignant and malignant lesions with some encouraging clinical outcomes. However, the molecular mechanisms of ALA-PDT in the therapeutic effect in HNC tumorigenesis and whether ALA-PDT as chemosensitizer for HNC treatment remain unclear. Accumulating data support cancer stem cells (CSCs) contributes chemo-resistance in HNC. Based on the previous studies, the purpose of the study is to investigate the effect of ALA-PDT on CSCs and chemosensitization property in HNC. Methodology/Principal Finding CSCs marker ALDH1 activity of HNC cells with ALA-PDT treatment as assessed by the Aldefluor assay flow cytometry analysis. Secondary Sphere-forming self-renewal, stemness markers expression, and invasiveness of HNC-CSCs with ALA-PDT treatment were presented. We observed that the treatment of ALA-PDT significantly down-regulated the ALDH1 activity and CD44 positivity of HNC-CSCs. Moreover, ALA-PDT reduced self-renewal property and stemness signatures expression (Oct4 and Nanog) in sphere-forming HNC-CSCs. ALA-PDT sensitized highly tumorigenic HNC-CSCs to conventional chemotherapies. Lastly, synergistic effect of ALA-PDT and Cisplatin treatment attenuated invasiveness/colongenicity property in HNC-CSCs. Conclusion/Significance Our results provide insights into the clinical prospect of ALA-PDT as a potential chemo-adjuvant therapy against head and neck cancer through eliminating CSCs property.
Derivatives of 5-Aminolevulinic Acid for Photodynamic Therapy
Ryan F. Donnelly, Paul A. McCarron and A. David Woolfson
Perspectives in Medicinal Chemistry , 2012,
Abstract: Photodynamic therapy (PDT) is a clinical treatment that combines the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitising drug (possessing no dark toxicity) to cause destruction of selected cells. Today, the most common agent used in dermatological PDT is 5-aminolevulinic acid (ALA). As a result of its hydrophilic character, ALA penetrates skin lesions poorly when applied topically. Its systemic bioavailability is limited and it is known to cause signifi cant side effects when given orally or intravenously. Numerous chemical derivatives of ALA have been synthesised with the aims of either improving topical penetration or enhancing systemic bioavailability, while reducing side effects. In vitro cell culture experiments with ALA derivatives have yielded promising results. However, if ALA derivatives are to demonstrate meaningful clinical benefi ts, a rational approach to topical formulation design is required, along with a systematic study aimed at uncovering the true potential of ALA derivatives in photodynamic therapy. With respect to systemic ALA delivery, more study is required in the developing area of ALA-containing dendrons and dendrimers.
5-Aminolevulinic Acid (5-ALA): Analysis of Preclinical and Safety Literature  [PDF]
Michael H. Perez, Beatriz L. Rodriguez, Terry T. Shintani, Keitaro Watanabe, Setsuko Miyanari, Rosanne C. Harrigan
Food and Nutrition Sciences (FNS) , 2013, DOI: 10.4236/fns.2013.410131

Problem: 5-ALA has been used for many years at relatively high dose amounts in single doses for photodynamic therapy and immunofluorescence of tumors. An analysis of compiled data relating to safety and any side-effects about the use of 5-ALA at low doses has not yet been published. Purpose: This report analyzes data about the safety of the use of 5-Aminolevulinic Acid (5-ALA) in low doses as a supplement over an extended period of time. Methods: This investigation is a systematic analysis of the current literature ((Medline, and SBI) and snowballing techniques) related to the safety and efficacy of 5-ALA in animals and humans. Clinical trials in progress using 5-ALA were also analyzed. Constant comparative analyses were used to synthesize the findings. Results: The safety of low-dose 5-ALA as a supplement has been demonstrated by animal and human studies. The results suggest that none of the investigations document the presence of symptoms or abnormal laboratory results of clinical significance. The minor laboratory changes documented were judged not clinically significant.

5-aminolevulinic acid-incorporated nanoparticles of methoxy poly(ethylene glycol)-chitosan copolymer for photodynamic therapy  [cached]
Chung CW,Chung KD,Jeong YI,Kang DH
International Journal of Nanomedicine , 2013,
Abstract: Chung-Wook Chung,1,* Kyu-Don Chung,2,* Young-Il Jeong,1 Dae Hwan Kang,1 1National Research and Development Center for Hepatobiliary Disease, Pusan National University Yangsan Hospital, Gyeongnam, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University, Seoul, Republic of Korea*These authors contributed equally to this workPurpose: The aim of this study was to make 5-aminolevulinic acid (5-ALA)-incorporated nanoparticles using methoxy polyethylene glycol/chitosan (PEG-Chito) copolymer for application in photodynamic therapy for colon cancer cells.Methods: 5-ALA-incorporated (PEG-Chito-5-ALA) nanoparticles were prepared by ion complex formation between 5-ALA and chitosan. Protoporphyrin IX accumulation in the tumor cells and phototoxicity induced by PEG-Chito-5-ALA nanoparticles were assessed using CT26 cells in vitro.Results: PEG-Chito-5-ALA nanoparticles have spherical shapes with sizes diameters 200 nm. More specifically, microscopic observation revealed a core-shell structure of PEG-Chito-5-ALA nanoparticles. 1H NMR spectra showed that 5-ALA was incorporated in the core of the nanoparticles. In the absence of light irradiation, all components such as 5-ALA, empty nanoparticles, and PEG-Chito-5-ALA nanoparticles did not affect the viability of cells. However, 5-ALA or PEG-Chito-5-ALA nanoparticles induced tumor cell death under light irradiation, and the viability of tumor cells was dose-dependently decreased according to the increase in irradiation time. In particular, PEG-Chito-5-ALA nanoparticles induced increased phototoxicity and higher protoporphyrin IX accumulation into the tumor cells than did 5-ALA alone. Furthermore, PEG-Chito-5-ALA nanoparticles accelerated apoptosis/necrosis of tumor cells, compared to 5-ALA alone.Conclusion: PEG-Chito-5-ALA nanoparticles showed superior delivery capacity of 5-ALA and phototoxicity against tumor cells. These results show that PEG-Chito-5-ALA nanoparticles are promising candidates for photodynamic therapy of colon cancer cells.Keywords: 5-ALA, photosensitizer, chitosan, nanoparticles, colon cancer, protoporphyrin IX
Evaluation of the efficacyof aminolevulinic acid-dependent photodynamic therapy on melanoma cancer cells treated with tocopherol succinate (in-vitro)  [cached]
Homa Kouchesfahani,Kazem Parivar,,Mohammad Nabiuni,Mohaddese Mohammadi-Sardoo
Zahedan Journal of Research in Medical Sciences , 2012,
Abstract: Background: Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) to produce an intracellular photo-sensitizer, a protoporphyrin molecule IX (PPIX) which absorbs light and targets cells, is a promising cancer treatment. Unfortunately, treatment failures are still a common occurrence when ALA is used. In this study, in order to enhance the efficacy of ALA-dependent photodynamic therapy, the effects of photodynamic therapy on melanoma cancer cells were studied after treating them with tocopherol succinate.Materials and Methods: In this experimental study melanoma cells were cultured in RPMI 1640 medium for 24 h. then, cells were treated with tocopherol succinate (6μm/ml). After 48 and 72 hours, the mediums were replaced by serum-free medium in the darkness, with ALA, 0.1mg/ml and then cells incubated for 4h. After that, cells were irradiated by using Nd: YAG laser (532 nm). After 24h, cell survival was measured by the MTT assay.Results: Twenty-four hours after PDT, among compared groups, pretreated cells with tocopherol succinate showed significant lower cell viability than control group. Conclusion: Induction of differentiation by using tocopherol succinate augmented intracellular PPIX accumulation in cells treated with ALA. Therefore phototoxic cell death after exposure to 532nm light enhances significantly in tocopherol succinate-pretreated cells. This study suggests that tocopherol succinate may act as a biological enhancer of ALA based photodynamic therapy
Effect of 5-aminolevulinic acid-based photodynamic therapy via reactive oxygen species in human cholangiocarcinoma cells
Kim CH, Chung CW, Choi KH, Yoo JJ, Kim DH, Jeong YI, Kang DH
International Journal of Nanomedicine , 2011, DOI: http://dx.doi.org/10.2147/IJN.S21395
Abstract: t of 5-aminolevulinic acid-based photodynamic therapy via reactive oxygen species in human cholangiocarcinoma cells Original Research (4114) Total Article Views Authors: Kim CH, Chung CW, Choi KH, Yoo JJ, Kim DH, Jeong YI, Kang DH Published Date June 2011 Volume 2011:6 Pages 1357 - 1363 DOI: http://dx.doi.org/10.2147/IJN.S21395 Cy Hyun Kim1,2, Chung-Wook Chung1, Kyung Ha Choi1, Jin-Ju Yoo1, Do Hyung Kim1,2, Young-IL Jeong1, Dae Hwan Kang1,2 1National Research and Development Center for Hepatobiliary Cancer, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea; 2School of Medicine, Pusan National University, Yangsan, Republic of Korea The first two authors contributed equally to this work. Abstract: Cancer cells have been reported to exhibit an enhanced capacity for protoporphyrin IX (PpIX) synthesis facilitated by the administration of 5-aminolevulinic acid (ALA). We investigated the effect of ALA-based photodynamic therapy (PDT) on human cholangiocarcinoma cells (HuCC-T1). Since protoporphyrin IX (PpIX), a metabolite of ALA, can produce reactive oxygen species (ROS) under irradiation and then induce phototoxicity, ALA-based PDT is a promising candidate for the treatment of cholangiocarcinoma. When various concentrations of ALA (0.05–2 mM) were used to treat HuCC-T1 cells for 6 or 24 hours, the intracellular PpIX level increased according to the ALA concentration and treatment time. Furthermore, an increased amount of PpIX in HuCC-T1 cells induced increased production of ROS by irradiation, resulting in increased phototoxicity.
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