Oncotarget

Research Papers:

Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas

Ja Eun Kim, Hye Rim Cho, Wen Jun Xu, Ji Young Kim, Sung Kwon Kim, Seung-Ki Kim, Sung-Hye Park, Hyeonjin Kim, Se-Hoon Lee, Seung Hong Choi, Sunghyouk Park and Chul-Kee Park _

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Oncotarget. 2015; 6:20266-20277. https://doi.org/10.18632/oncotarget.4060

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Abstract

Ja Eun Kim1,*, Hye Rim Cho2,*, Wen Jun Xu3,*, Ji Young Kim1, Sung Kwon Kim4, Seung-Ki Kim1,5, Sung-Hye Park6, Hyeonjin Kim2, Se-Hoon Lee7, Seung Hong Choi2, Sunghyouk Park3 and Chul-Kee Park1

1 Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea

2 Department of Radiology, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea

3 College of Pharmacy, Natural Product Research Institute, Seoul National University, Sillim-dong, Gwanak-gu, Seoul, Korea

4 Department of Neurosurgery, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Korea

5 Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Jongno-gu, Seoul, Korea

6 Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea

7 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

* These authors have contributed equally to this work

Correspondence to:

Chul-Kee Park, email:

Sunghyouk Park, email:

Seung Hong Choi, email:

Keywords: brain tumors, oncology, 5-ALA, fluorescence, IDH1, glioma, NADPH

Received: March 01, 2015 Accepted: April 22, 2015 Published: May 10, 2015

Abstract

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has become the main treatment modality in malignant gliomas. However unlike glioblastomas, there are inconsistent result about fluorescence status in WHO grade III gliomas. Here, we show that mutational status of IDH1 is linked to 5-ALA fluorescence. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) IDH1, we demonstrated a lag in 5-ALA metabolism and accumulation of protoporphyrin IX (PpIX) in U87MG-IDH1R132Hcells. Next, we used liquid chromatography–mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes caused by 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. High levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporarily enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. In conclusion, we have discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Low levels of NADPH in tumors with mutated IDH1 is responsible for the enhanced fluorescence.


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