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Metformin enhanced in vitro radiosensitivity associates with G2/M cell cycle arrest and elevated adenosine-5’-monophosphate-activated protein kinase levels in glioblastoma

Sebastian Adeberg
Sebastian Adeberg
, 
Denise Bernhardt
Denise Bernhardt
, 
Semi B. Harrabi
Semi B. Harrabi
, 
Nils H. Nicolay
Nils H. Nicolay
, 
Juliane Hörner-Rieber
Juliane Hörner-Rieber
, 
Laila König
Laila König
, 
Michael Repka
Michael Repka
, 
Angela Mohr
Angela Mohr
, 
Amir Abdollahi
Amir Abdollahi
, 
Klaus-Josef Weber
Klaus-Josef Weber
, 
Juergen Debus
Juergen Debus
 et 
Stefan Rieken
Stefan Rieken
   | 01 nov. 2017
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Article Category: Research Article
Publié en ligne: 01 nov. 2017
Pages: 431 - 437
Reçu: 12 févr. 2017
Accepté: 30 sept. 2017
DOI: https://doi.org/10.1515/raon-2017-0042
© 2017 Sebastian Adeberg, Denise Bernhardt, Semi B. Harrabi, Nils H. Nicolay, Juliane Hörner-Rieber, Laila König, Michael Repka, Angela Mohr, Amir Abdollahi, Klaus-Josef Weber, Juergen Debus, Stefan Rieken
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Figure 1

(A,B) Clonogenic survival assays of LN229 and LN18 glioblastoma cell lines after treatment with photon irradiation. (C,D) Clonogenic survival assays after comparing LN229 and LN18 cell lines after combined treatment with TMZ (C) or metformin (D). Error bars represent standard deviations. * shows a statistical significance (P <0.05). In LN229 enhanced cell kill was observed by TMZ and in LN18 cells lines metformin treatment resulted in increased cell toxicity compared to the control, as well as the combination of both agents itself. Combined bimodal and trimodal treatment results in superior cell toxicity.
(A,B) Clonogenic survival assays of LN229 and LN18 glioblastoma cell lines after treatment with photon irradiation. (C,D) Clonogenic survival assays after comparing LN229 and LN18 cell lines after combined treatment with TMZ (C) or metformin (D). Error bars represent standard deviations. * shows a statistical significance (P <0.05). In LN229 enhanced cell kill was observed by TMZ and in LN18 cells lines metformin treatment resulted in increased cell toxicity compared to the control, as well as the combination of both agents itself. Combined bimodal and trimodal treatment results in superior cell toxicity.

Figure 2

(A) In LN229 pAMPK measurements were significantly increased after treatment with Metformin, 2 Gy and temozolomide and 6 Gy combined with Metformin compared to the control if not otherwise specified (* p<0.05). (B) No significant increase of pAMPK levels were observed in cell line LN18. Error bars represent standard deviation.
(A) In LN229 pAMPK measurements were significantly increased after treatment with Metformin, 2 Gy and temozolomide and 6 Gy combined with Metformin compared to the control if not otherwise specified (* p<0.05). (B) No significant increase of pAMPK levels were observed in cell line LN18. Error bars represent standard deviation.

Sensitizer enhancement ratio (SER 20%) for LN229 and LN18 cells after treatment with metformin, temozolomide (TMZ) and combined treatment with 2Gy irradiation

SER (20% survival) / 2 Gy
Cell lineLN18LN229
50 µM TMZ1.112.15
1mM Metformin0.670.74
20 mM Metformin3.130.61
50 µM TMZ + 20mM Metformin2.572.69

Cell cycle distribution into G1, S, and G2/M phase of LN18 and LN229 cells after various treatments. Measurements were performed after 72h. * shows a statistical significance (P <0.05) of the treatment compared to the control

Ln18 24h72hG1 (%) ± sth.dev.S (%) ± sth.dev.G2/M (%) ± sth.dev.
Ctrl74.5 ± 85.6 ± 019.9 ± 1
50µM TMZ66.0 ± 89.5 ± 124.6 ± 3
1mM Metformin71.0 ± 56.3 ± 122.7 ± 0
20mM Metformin46.9 ± 39.3 ± 243.8 ± 2*
50µM TMZ + 1mM Metformin64.5 ± 08.6 ± 426.9 ± 4
50µM TMZ + 20mM Metformin41.2 ± 019.4 ± 739.4 ± 2
2Gy71.7 ± 17.5 ± 120.8 ± 4
6Gy56.2 ± 58.0 ± 135.7 ± 1
2Gy + 50µM TMZ62.0 ± 56.6 ± 531.4 ± 4
2Gy + 1mM Metformin68.2 ± 710.3 ± 121.5 ± 2
2 Gy + 20mM Metformin41.3 ± 016.1 ± 142.6 ± 4*
2Gy + 50µM TMZ + 1mM Metformin60.1 ± 78.6 ± 131.3 ± 0
2Gy + 50µM TMZ + 20mM Metformin33.5 ± 220.0 ± 346.5 ± 4*
6Gy + 50µM TMZ47.1 ± 711.6 ± 341.3 ± 3*
6Gy + 1mM Metformin51.3 ± 210.4 ± 038.2 ± 3
6Gy + 20mM Metformin36.1 ± 314.2 ± 049.7 ± 3*
6Gy + 50µM TMZ + 1mM Metformin46.3 ± 410.7 ± 142.9 ± 2*
6Gy + 50µM TMZ + 20mM Metformin27.9 ± 114.1 ± 358.0 ± 2*
Ln229 24h72hG1 (%)S (%)G2/M (%)
Ctrl86.0 ± 23.6 ± 210.4 ± 2
50µM TMZ37.4 ± 38.1 ± 254.6 ± 5*
1mM Metformin87.4 ± 33.3 ± 19.3 ± 0
20mM Metformin63.9 ± 1014.9 ± 121.2 ± 9
50µM TMZ + 1mM Metformin38.9 ± 06.1 ± 255.0 ± 4*
50µM TMZ + 20mM Metformin25.2 ± 125.4 ± 249.4 ± 2*
2Gy83.5 ± 53.3 ± 213.2 ± 5
6Gy67.1 ± 26.2 ± 126.7 ± 1
2Gy + 50µM TMZ44.4 ± 16.9 ± 148.7 ± 4*
2Gy + 1mM Metformin82.3 ± 13.5 ± 114.2 ± 2
2 Gy + 20mM Metformin55.6 ± 211.8 ± 232.6 ± 1 *
2Gy + 50µM TMZ + 1mM Metformin46.0 ± 17.9 ± 146.1 ± 0*
2Gy + 50µM TMZ + 20mM Metformin32.3 ± 328.9 ± 738.8 ± 5*
6Gy + 50µM TMZ41.6 ± 28.9 ± 349.5 ± 3
6Gy + 1mM Metformin55.5 ± 118.8 ± 435.7 ± 23
6Gy + 20mM Metformin56.5 ± 187.8 ± 635.7 ± 16
6Gy + 50µM TMZ + 1mM Metformin41.9 ± 25.9 ± 252.2 ± 2*
6Gy + 50µM TMZ + 20mM Metformin18.4 ± 116.2 ± 365.4 ± 3*
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Medicine, Clinical Medicine, Radiology, Internal Medicine, Haematology, Oncology
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