Skip to main content

Advertisement

SpringerLink
Log in

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

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  3. Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008;62:753–64.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  28. Heinemann IU, Jahn M, Jahn D. The biochemistry of heme biosynthesis. Arch Biochem Biophys. 2008;474:238–51.

    Article  PubMed  CAS  Google Scholar 

  29. Krishnamurthy P, Xie T, Schuetz JD. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther. 2007;114:345–58.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by grants from the National Basic Research Program of China (2009CB526404 S.Z.), the Natural Science Foundation of China (30973078 S.Z. 30901533 Y.L. 81172388 Y.L.) and Foundation of Harbin Science and Technology Committee (2007AA3C0832 S.Z.). We gratefully acknowledge Dr. John D. Schuetz (Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN) for providing the ABCB6 plasmid used in this study.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The First Clinical College of Harbin Medical University, Harbin, People’s Republic of China

    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, Yao-Hua Liu MD, PhD & Bing-Jie Zheng MD, PhD

  2. Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, People’s Republic of China

    Da-Yong Wang MD & Xu Gao MD, PhD

  3. New York University Langone Medical Center and School of Medicine, New York, NY, USA

    Chen Shi BSc

  4. Section of Neurosurgery, Department of Surgery, The University of Chicago Medical Center and Pritzker School of Medicine, Chicago, IL, USA

    Chang-Bin Shi MD, PhD

  5. Department of Neurosurgery, Klinikum Augsburg, Augsburg, Germany

    Nikolai G. Rainov MD, PhD

Authors
  1. Shi-Guang Zhao MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Feng Chen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li-Gang Wang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guang Yang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Da-Yong Han MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lei Teng MD PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ming-Chun Yang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Da-Yong Wang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chen Shi BSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yao-Hua Liu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bing-Jie Zheng MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chang-Bin Shi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xu Gao MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nikolai G. Rainov MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shi-Guang Zhao MD, PhD.

Additional information

Shi-Guang Zhao, Xiao-Feng Chen and Li-Gang Wang contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 307 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, SG., Chen, XF., Wang, LG. et al. Increased Expression of ABCB6 Enhances Protoporphyrin IX Accumulation and Photodynamic Effect in Human Glioma. Ann Surg Oncol 20, 4379–4388 (2013). https://doi.org/10.1245/s10434-011-2201-6

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-011-2201-6

Keywords

Search

Navigation