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GdCl3 Induced Hep G2 Cell Death through Mitochondrial and External Death Pathways without Significant Elevation of ROS Generation

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Abstract

Gadolinium (Gd) compounds have important applications as MRI contrast and potential anticancer agents. The present study investigated the mechanisms of the proapoptotic effect of gadolinium chloride (GdCl3) on hepatoblastoma cell line (Hep G2) tumor cells. The experimental results indicated that GdCl3 induced apoptosis of Hep G2 at high concentration and with long time incubation; however, unlike the actions on normal cell lines, GdCl3 did not cause any oxidative stress on tumor cells. Cytochrome c (Cyt c) and apoptosis inducing factor release, Bax translocation, collapse of mitochondria membrane potential, caspase 3 and 8 activation, and Bid cleavage were observed along with a sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK). Addition of ERK and JNK inhibitor attenuated the effect of GdCl3 induced apoptosis and Cyt c release. All the results suggested a novel mechanism that GdCl3 induced Hep G2 cell death through intrinsic and external death pathways without significant elevation of reactive oxygen species generation. The present work provided new insight to understand the mechanisms of the biological effects of GdCl3 and implications for the development of anticancer Gd agents.

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Abbreviations

GdCl3 :

Gadolinium chloride

Hep G2:

Hepatoblastoma cell line

DMEM:

Dulbecco’s modified eagle’s medium

FBS:

Fetal bovine serum

AIF:

Apoptosis inducing factor

Cyt c:

Cytochrome c

CsA:

Cyclosporin A

ROS:

Reactive oxygen species

MTT:

3-(4, 5-Dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide

PBS:

Phosphate-buffered saline

PI:

Propidium iodide

DCFH-DA:

2′, 7′-dichlorofluorescein diacetate

JC-1:

5, 5′, 6, 6′-tetrachloro-1, 1′, 3, 3′-tetraethyl benzimidazol carbocyanine iodide

FITC:

Fluorescein isothiocyanate

LCFM:

Laser confocal fluorescence microscopy

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (nos. 20671008 and 20971008).

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Authors and Affiliations

  1. State Key Laboratories of Natural and Biomimetic Drugs, Peking University, Beijing, 100083, People’s Republic of China

    Lihua Ye, Xiaoda Yang & Kui Wang

  2. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100083, People’s Republic of China

    Zhe Shi & Huixue Liu

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  1. Lihua Ye
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  2. Zhe Shi
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  3. Huixue Liu
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  4. Xiaoda Yang
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  5. Kui Wang
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Correspondence to Huixue Liu or Xiaoda Yang.

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Ye, L., Shi, Z., Liu, H. et al. GdCl3 Induced Hep G2 Cell Death through Mitochondrial and External Death Pathways without Significant Elevation of ROS Generation. Biol Trace Elem Res 151, 148–155 (2013). https://doi.org/10.1007/s12011-012-9538-y

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  • DOI: https://doi.org/10.1007/s12011-012-9538-y

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