Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 13/2013

01-12-2013 | Translational Research and Biomarkers

Increased Expression of ABCB6 Enhances Protoporphyrin IX Accumulation and Photodynamic Effect in Human Glioma

Authors: Shi-Guang Zhao, MD, PhD, Xiao-Feng Chen, MD, PhD, Li-Gang Wang, MD, PhD, Guang Yang, MD, PhD, Da-Yong Han, MD, Lei Teng, MD PhD, Ming-Chun Yang, MD, PhD, Da-Yong Wang, MD, Chen Shi, BSc, Yao-Hua Liu, MD, PhD, Bing-Jie Zheng, MD, PhD, Chang-Bin Shi, MD, PhD, Xu Gao, MD, PhD, Nikolai G. Rainov, MD, PhD

Published in: Annals of Surgical Oncology | Issue 13/2013

Login to get access

Abstract

Background

Glioma recurrence usually occurs close to the tumor resection margins as a result of residual infiltrating glioma cells. 5-aminolevulinic acid (ALA) fluorescence-guided resection of gliomas has been demonstrated to enhance discrimination of tumor tissue and to improve survival. ALA-based photodynamic therapy is an effective albeit still experimental adjuvant treatment option for gliomas. However, insufficient protoporphyrin IX (PpIX) accumulation may limit the benefits of fluorescence-guided resection and photodynamic therapy.

Methods

We investigated the expression of the ATP-binding cassette transporter ABCB6, which regulates porphyrin synthesis, in surgical specimens from human gliomas and manipulated ABCB6 in human glioma cell lines.

Results

Our findings demonstrated that expression levels of ABCB6 were greatly elevated in human gliomas compared with normal brain tissues and correlated with World Health Organization histologic grade. A previously undescribed finding was that ABCB6 mRNA expression in solidly fluorescing tumor tissues was higher than that in vaguely fluorescing tumors, suggesting that ABCB6 may be at least in part responsible for PpIX accumulation in glioma cells. Accordingly, ABCB6 overexpression in glioma cell lines caused a marked increase in intracellular levels of PpIX, and was more sensitive to ALA-induced photodynamic therapy—events that could be prevented by silencing ABCB6 via siRNA treatment.

Conclusions

Our findings indicate a crucial role of ABCB6 in ALA metabolism and accumulation of PpIX in glioma. ABCB6 overexpression is a potential approach to enhance accumulation of PpIX for optimizing the subjective discrimination of vague fluorescence and improving the efficacy of ALA-based photodynamic therapy.
Appendix
Available only for authorised users
Literature
1.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.PubMedCrossRef
2.
Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95:190–8.PubMedCrossRef
3.
Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008;62:753–64.PubMedCrossRef
4.
Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 1989;16:1405–9.PubMedCrossRef
5.
Aydin H, Sillenberg I, von Lieven H. Patterns of failure following CT-based 3-D irradiation for malignant glioma. Strahlenther Onkol. 2001;177:424–31.PubMedCrossRef
6.
Stummer W, Stocker S, Wagner S, Stepp H, Fritsch C, Goetz C, et al. Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery. 1998;42:518–25.PubMedCrossRef
7.
Stummer W, Stocker S, Novotny A, Heimann A, Sauer O, Kempski O, et al. In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. J Photochem Photobiol B. 1998;45:160–9.PubMedCrossRef
8.
Stummer W, Stepp H, Moller G, Ehrhardt A, Leonhard M, Reulen HJ. Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir (Wien). 1998;140:995–1000.PubMedCrossRef
9.
Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg. 2000;93:1003–13.PubMedCrossRef
10.
Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7:392–401.PubMedCrossRef
11.
Wu SM, Ren QG, Zhou MO, Peng Q, Chen JY. Protoporphyrin IX production and its photodynamic effects on glioma cells, neuroblastoma cells and normal cerebellar granule cells in vitro with 5-aminolevulinic acid and its hexylester. Cancer Lett. 2003;200:123–31.PubMedCrossRef
12.
Utsuki S, Oka H, Sato S, Shimizu S, Suzuki S, Tanizaki Y, et al. Possibility of using laser spectroscopy for the intraoperative detection of nonfluorescing brain tumors and the boundaries of brain tumor infiltrates. J Neurosurg. 2006;104:618–20.PubMedCrossRef
13.
Hefti M, von Campe G, Moschopulos M, Siegner A, Looser H, Landolt H. 5-Aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institution. Swiss Med Wkly. 2008;138:180–5.PubMed
14.
Madsen SJ, Angell-Petersen E, Spetalen S, Carper SW, Ziegler SA, Hirschberg H. Photodynamic therapy of newly implanted glioma cells in the rat brain. Lasers Surg Med. 2006;38:540–8.PubMedCrossRef
15.
Norum OJ, Selbo PK, Weyergang A, Giercksky KE, Berg K. Photochemical internalization (PCI) in cancer therapy: from bench towards bedside medicine. J Photochem Photobiol B. 2009;96:83–92.PubMedCrossRef
16.
Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, et al. Identification of a mammalian mitochondrial porphyrin transporter. Nature. 2006;443:586–9.PubMedCrossRef
17.
Liu Y, Zhang X, Liang Y, Yu H, Chen X, Zheng T, et al. Targeting X box-binding protein-1 (XBP1) enhances sensitivity of glioma cells to oxidative stress. Neuropathol Appl Neurobiol. 2011;37:395–405.PubMedCrossRef
18.
Smits T, Robles CA, van Erp PE, van de Kerkhof PC, Gerritsen MJ. Correlation between macroscopic fluorescence and protoporphyrin IX content in psoriasis and actinic keratosis following application of aminolevulinic acid. J Invest Dermatol. 2005;125:833–9.PubMedCrossRef
19.
Smits T, van Laarhoven AI, Staassen A, van de Kerkhof PC, van Erp PE, Gerritsen MJ. Induction of protoporphyrin IX by aminolaevulinic acid in actinic keratosis, psoriasis and normal skin: preferential porphyrin enrichment in differentiated cells. Br J Dermatol. 2009;160:849–57.PubMedCrossRef
20.
Sinha AK, Anand S, Ortel BJ, Chang Y, Mai Z, Hasan T, et al. Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells. Br J Cancer. 2006;95:485–95.PubMedCrossRef
21.
Wang H, Zhang SY, Wang S, Lu JA, Wu W, Weng L, et al. REV3L confers chemoresistance to cisplatin in human gliomas: the potential of its RNAi for synergistic therapy. Neurooncology. 2009;11:790–802.
22.
Yang J, Xia Y, Liu X, Jiang S, Xiong L. Desferrioxamine shows different potentials for enhancing 5-aminolaevulinic acid-based photodynamic therapy in several cutaneous cell lines. Lasers Med Sci. 2010;25:251–7.PubMedCrossRef
23.
Bourre L, Giuntini F, Eggleston IM, Wilson M, MacRobert AJ. 5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy. Mol Cancer Ther. 2008;7:1720–9.PubMedCrossRef
24.
Teng L, Nakada M, Zhao SG, Endo Y, Furuyama N, Nambu E, et al. Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy. Br J Cancer. 2011;104:798–807.PubMedCrossRef
25.
Kemmner W, Wan K, Ruttinger S, Ebert B, Macdonald R, Klamm U, et al. Silencing of human ferrochelatase causes abundant protoporphyrin-IX accumulation in colon cancer. FASEB J. 2008;22:500–9.PubMedCrossRef
26.
Anand S, Honari G, Hasan T, Elson P, Maytin EV. Low-dose methotrexate enhances aminolevulinate-based photodynamic therapy in skin carcinoma cells in vitro and in vivo. Clin Cancer Res. 2009;15:3333–43.PubMedCrossRef
27.
Zhou S, Zong Y, Ney PA, Nair G, Stewart CF, Sorrentino BP. Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels. Blood. 2005;105:2571–6.PubMedCrossRef
28.
Heinemann IU, Jahn M, Jahn D. The biochemistry of heme biosynthesis. Arch Biochem Biophys. 2008;474:238–51.PubMedCrossRef
29.
Krishnamurthy P, Xie T, Schuetz JD. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther. 2007;114:345–58.PubMedCrossRef
30.
Rebeiz N, Arkins S, Kelley KW, Rebeiz CA. Enhancement of coproporphyrinogen III transport into isolated transformed leukocyte mitochondria by ATP. Arch Biochem Biophys. 1996;333:475–81.PubMedCrossRef
31.
Koller ME. Studies on the uptake of porphyrin by isolated rat liver mitochondria with particular emphasis on the effect of hemin. FEBS Lett. 1979;100:47–51.PubMedCrossRef
32.
Paterson JK, Shukla S, Black CM, Tachiwada T, Garfield S, Wincovitch S, et al. Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane. Biochemistry. 2007;46:9443–52.PubMedCrossRef
33.
Hebeda KM, Saarnak AE, Olivo M, Sterenborg HJ, Wolbers JG. 5-Aminolevulinic acid induced endogenous porphyrin fluorescence in 9L and C6 brain tumours and in the normal rat brain. Acta Neurochir (Wien). 1998;140:503–12.PubMedCrossRef
34.
Buytaert E, Dewaele M, Agostinis P. Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. Biochim Biophys Acta. 2007;1776:86–107.PubMed
35.
Madsen SJ, Mathews MS, Angell-Petersen E, Sun CH, Vo V, Sanchez R, et al. Motexafin gadolinium enhances the efficacy of aminolevulinic acid mediated–photodynamic therapy in human glioma spheroids. J Neurooncol. 2009;91:141–9.PubMedCrossRef
36.
Inoue H, Kajimoto Y, Shibata MA, Miyoshi N, Ogawa N, Miyatake S, et al. Massive apoptotic cell death of human glioma cells via a mitochondrial pathway following 5-aminolevulinic acid-mediated photodynamic therapy. J Neurooncol. 2007;83:223–31.PubMedCrossRef
37.
Karmakar S, Banik NL, Patel SJ, Ray SK. 5-Aminolevulinic acid-based photodynamic therapy suppressed survival factors and activated proteases for apoptosis in human glioblastoma U87MG cells. Neurosci Lett. 2007;415:242–7.PubMedCrossRef
Metadata
Title
Increased Expression of ABCB6 Enhances Protoporphyrin IX Accumulation and Photodynamic Effect in Human Glioma
Authors
Shi-Guang Zhao, MD, PhD
Xiao-Feng Chen, MD, PhD
Li-Gang Wang, MD, PhD
Guang Yang, MD, PhD
Da-Yong Han, MD
Lei Teng, MD PhD
Ming-Chun Yang, MD, PhD
Da-Yong Wang, MD
Chen Shi, BSc
Yao-Hua Liu, MD, PhD
Bing-Jie Zheng, MD, PhD
Chang-Bin Shi, MD, PhD
Xu Gao, MD, PhD
Nikolai G. Rainov, MD, PhD
Publication date
01-12-2013
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue 13/2013
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-011-2201-6

Other articles of this Issue 13/2013

Annals of Surgical Oncology 13/2013 Go to the issue

Gastrointestinal Oncology

Quality of Life After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An Asian Perspective

Hepatobiliary Tumors

A Randomized Phase II Trial of Three Intensified Chemotherapy Regimens in First-Line Treatment of Colorectal Cancer Patients with Initially Unresectable or Not Optimally Resectable Liver Metastases. The METHEP Trial

Urologic Oncology

Validation of the MSKCC and Heng Risk Criteria Models for Predicting Survival in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib

Melanomas

Epitrochlear Lymph Node Dissection and Axillary Lymph Node Biopsy. An Unusual Clinical Presentation in a Patient with Forearm Melanoma

Breast Oncology

Radioactive Seed Localization Compared to Wire Localization in Breast-Conserving Surgery: Initial 6-Month Experience

Healthcare Policy and Outcomes

Race Does Not Impact Pancreatic Cancer Treatment and Survival in an Equal Access Federal Health Care System