Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy

Background:Recurrence of glioma frequently occurs within the marginal area of the surgical cavity due to invading residual cells. 5-Aminolevulinic acid (5-ALA) fluorescence-guided resection has been used as effective therapeutic modalities to improve discrimination of brain tumour margins and patient prognosis. However, the marginal areas of glioma usually show vague fluorescence, which makes tumour identification difficult, and the applicability of 5-ALA-based photodynamic therapy (PDT) is hampered by insufficient therapeutic efficacy in glioma tissues.Methods:To overcome these issues, we assessed the expression of ferrochelatase (FECH) gene, which encodes a key enzyme that catalyses the conversion of protoporphyrin IX (PpIX) to heme, in glioma surgical specimens and manipulated FECH in human glioma cell lines.Results:Prominent downregulation of FECH mRNA expression was found in glioblastoma tissues compared with normal brain tissues, suggesting that FECH is responsible for PpIX accumulation in glioblastoma cells. Depletion of FECH by small interference RNA enhanced PpIX fluorescence after exposure to 5-ALA concomitant with increased intracellular PpIX accumulation in glioma cells. Silencing of FECH caused marked growth inhibition and apoptosis induction by PDT in glioma cells.Conclusion:These results suggest that knockdown of FECH is a potential approach to enhance PpIX fluorescent quality for optimising the subjective discrimination of vague fluorescence and improving the effect of 5-ALA-PDT.

[1]  T. Hasan,et al.  Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells , 2006, British Journal of Cancer.

[2]  N. Sugimoto,et al.  Sphingosine‐1‐phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival , 2010, International journal of cancer.

[3]  Y. Kajimoto,et al.  Massive apoptotic cell death of human glioma cells via a mitochondrial pathway following 5-aminolevulinic acid-mediated photodynamic therapy , 2007, Journal of Neuro-Oncology.

[4]  Isabelle Camby,et al.  Present and potential future issues in glioblastoma treatment , 2006, Expert review of anticancer therapy.

[5]  K. Wallner,et al.  Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. , 1989, International journal of radiation oncology, biology, physics.

[6]  B. Wilson,et al.  Photodynamic therapy for recurrent supratentorial gliomas. , 1995, Seminars in surgical oncology.

[7]  J Hanania,et al.  The effect of EDTA and serum on endogenous porphyrin accumulation and photodynamic sensitization of human K562 leukemic cells. , 1992, Cancer letters.

[8]  H. Daniel,et al.  Study of the mechanisms of uptake of 5-aminolevulinic acid derivatives by PEPT1 and PEPT2 transporters as a tool to improve photodynamic therapy of tumours. , 2006, The international journal of biochemistry & cell biology.

[9]  N. Banik,et al.  5-Aminolevulinic acid-based photodynamic therapy suppressed survival factors and activated proteases for apoptosis in human glioblastoma U87MG cells , 2007, Neuroscience Letters.

[10]  J Moan,et al.  5‐Aminolevulinic acid‐based photodynamic therapy , 1997, Cancer.

[11]  H Stepp,et al.  Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. , 2000, Journal of neurosurgery.

[12]  Z. Malik,et al.  Differentiation-dependent photodynamic therapy regulated by porphobilinogen deaminase in B16 melanoma , 2004, British Journal of Cancer.

[13]  T. Lei,et al.  RNA interference therapy for glioblastoma , 2010, Expert opinion on biological therapy.

[14]  K. Fujii,et al.  Possibility of using laser spectroscopy for the intraoperative detection of nonfluorescing brain tumors and the boundaries of brain tumor infiltrates. Technical note. , 2006, Journal of neurosurgery.

[15]  W. Stummer,et al.  Technical Principles for Protoporphyrin-IX-Fluorescence Guided Microsurgical Resection of Malignant Glioma Tissue , 1998, Acta Neurochirurgica.

[16]  S. To,et al.  Differential effects of photofrin, 5-aminolevulinic acid and calphostin C on glioma cells. , 2006, Journal of photochemistry and photobiology. B, Biology.

[17]  R. Keep,et al.  PEPT2-mediated transport of 5-aminolevulinic acid and carnosine in astrocytes , 2006, Brain Research.

[18]  Henry Hirschberg,et al.  Determination of fluence rate and temperature distributions in the rat brain; implications for photodynamic therapy. , 2007, Journal of biomedical optics.

[19]  D. Vernon,et al.  Endogenous porphyrin distribution induced by 5-aminolaevulinic acid in the tissue layers of the gastrointestinal tract. , 1993, Journal of photochemistry and photobiology. B, Biology.

[20]  M. Westphal,et al.  Biological and karyotypic characterization of a new cell line derived from human gliosarcoma. , 1988, Cancer research.

[21]  M. Berens,et al.  Ephrin-B3 ligand promotes glioma invasion through activation of Rac1. , 2006, Cancer research.

[22]  H. Matsui,et al.  Mechanisms involved in delta-aminolevulinic acid (ALA)-induced photosensitivity of tumor cells: relation of ferrochelatase and uptake of ALA to the accumulation of protoporphyrin. , 2005, Biochemical pharmacology.

[23]  L. Gossner,et al.  Photodynamic ablation of high-grade dysplasia and early cancer in Barrett's esophagus by means of 5-aminolevulinic acid. , 1998, Gastroenterology.

[24]  G. C. Ferreira,et al.  Structure and function of ferrochelatase , 1995, Journal of bioenergetics and biomembranes.

[25]  K. T. Moesta,et al.  Silencing of human ferrochelatase causes abundant protoporphyrin‐IX accumulation in colon cancer , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  H. Hirschberg,et al.  Motexafin gadolinium enhances the efficacy of aminolevulinic acid mediated-photodynamic therapy in human glioma spheroids , 2008, Journal of Neuro-Oncology.

[27]  W. Stummer,et al.  Transport of 5-aminolevulinic acid between blood and brain , 2003, Brain Research.

[28]  J C Kennedy,et al.  Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. , 1992, Journal of photochemistry and photobiology. B, Biology.

[29]  W. Stummer,et al.  In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. , 1998, Journal of photochemistry and photobiology. B, Biology.

[30]  Saroj P. Mathupala,et al.  RNAi Based Approaches to the Treatment of Malignant Glioma , 2006, Technology in cancer research & treatment.

[31]  M. Miyake,et al.  siRNA‐mediated Knockdown of the Heme Synthesis and Degradation Pathways: Modulation of Treatment Effect of 5‐Aminolevulinic Acid‐based Photodynamic Therapy in Urothelial Cancer Cell Lines , 2009, Photochemistry and photobiology.

[32]  A. Obwegeser,et al.  Photodynamic therapy in neurosurgery: a review. , 1996, Journal of photochemistry and photobiology. B, Biology.

[33]  Gabriele Schackert,et al.  Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. , 2008, Neuro-oncology.

[34]  Mitsutoshi Nakada,et al.  EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion. , 2005, The American journal of pathology.

[35]  H Stepp,et al.  Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. , 1998, Neurosurgery.

[36]  G. Iacob,et al.  Current data and strategy in glioblastoma multiforme , 2009, Journal of medicine and life.

[37]  W. Pardridge.  Intravenous, non-viral RNAi gene therapy of brain cancer , 2004, Expert opinion on biological therapy.

[38]  M. Berens,et al.  Determinants of human astrocytoma migration. , 1994, Cancer research.

[39]  K. Berg,et al.  Photochemical internalization (PCI) in cancer therapy: from bench towards bedside medicine. , 2009, Journal of photochemistry and photobiology. B, Biology.

[40]  Kai Chen,et al.  Role of the c-Jun N-terminal kinase signaling pathway in SW480 cell apoptosis in response to 5-aminolevulinic acid-based photodynamic therapy , 2008 .

[41]  H. Aydin,et al.  Patterns of Failure Following CT-Based 3-D Irradiation for Malignant Glioma , 2001, Strahlentherapie und Onkologie.

[42]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[43]  Sachio Suzuki,et al.  Auditory alert system for fluorescence-guided resection of gliomas. , 2008, Neurologia medico-chirurgica.

[44]  Webster K. Cavenee,et al.  Erratum: The 2007 WHO classification of tumours of the central nervous system (Acta Neuropathol (2007) vol. 114 (97-109)) , 2007 .

[45]  B. Van Houten,et al.  Mitochondrial and nuclear DNA damage induced by 5-aminolevulinic acid. , 2004, Archives of biochemistry and biophysics.

[46]  A. Aigner,et al.  RNA interference-mediated gene silencing of pleiotrophin through polyethylenimine-complexed small interfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts. , 2006, Human gene therapy.

[47]  F. Zanella,et al.  Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. , 2006, The Lancet. Oncology.