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Vanadium compounds discriminate hepatoma and normal hepatic cells by differential regulation of reactive oxygen species

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Abstract

Our previous study indicated that vanadium compounds can block cell cycle progression at the G1/S phase in human hepatoma HepG2 cells via a highly activated extracellular signal-regulated protein kinase (ERK) signal. To explore their differential action on normal cells, we investigated the response of an immortalized hepatic cell line, L02 cells. The results demonstrated that a higher concentration of vanadium compounds was needed to inhibit L02 proliferation, which was associated with S and G2/M cell cycle arrest. In addition, in contrast to insignificant reactive oxygen species (ROS) generation in HepG2 cells, all of the vanadium compounds resulted significant increases in both O ·−2 and H2O2 levels in L02 cells. At the same time, ERK and c-Jun N-terminal kinase (JNK) as well as cell division control protein 2 homolog (Cdc2) were found to be highly phosphorylated, which could be counteracted with the antioxidant N-acetylcysteine (NAC). The current study also demonstrated that both the ERK and the JNK pathways contributed to the cell cycle arrest induced by vanadium compounds in L02 cells. More importantly, it was found that although NAC can ameliorate the cytotoxicity of vanadium compounds in L02 cells, it did not decrease their cytotoxicity in HepG2 cells. It thus shed light on the potential therapeutic applications of vanadium compounds with antioxidants as synergistic agents to reduce their toxicities in human normal cells without affecting their antitumor activities in cancer cells.

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Abbreviations

Akt/PKB:

Protein kinase B

Cdc2/Cdk1:

Cell division control protein 2 homolog/cyclin dependent kinase 1

CM-H2DCF-DA:

5-(and-6)-Chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate

ERK:

Extracellular signal-regulated protein kinase

FBS:

Fetal bovine serum

HE:

Dihydroethidium

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide

NAC:

N-acetylcysteine

NaVO3 :

Sodium metavanadate

PI3-K:

Phosphatidylinositol 3-kinase

pRb:

Retinoblastoma tumor suppressor protein

ROS:

Reactive oxygen species

VO(acac)2 :

Bis(acetylacetonato)-oxovanadium(IV)

VO(ma)2 :

Bis(maltolato)-oxovanadium(IV)

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (20871008) and the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry.

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Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People’s Republic of China

    Qin Wang, Tong-Tong Liu & Kui Wang

  2. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People’s Republic of China

    Qin Wang, Tong-Tong Liu, Ying Fu, Kui Wang & Xiao-Gai Yang

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  1. Qin Wang
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  2. Tong-Tong Liu
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  3. Ying Fu
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  4. Kui Wang
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Correspondence to Xiao-Gai Yang.

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Wang, Q., Liu, TT., Fu, Y. et al. Vanadium compounds discriminate hepatoma and normal hepatic cells by differential regulation of reactive oxygen species. J Biol Inorg Chem 15, 1087–1097 (2010). https://doi.org/10.1007/s00775-010-0668-4

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