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A novel dithiocarbamate derivative induces cell apoptosis through p53-dependent intrinsic pathway and suppresses the expression of the E6 oncogene of human papillomavirus 18 in HeLa cells

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Abstract

Dithiocarbamates (DTCs) exhibit a broad spectrum of antitumor activities, however, their molecular mechanisms of antitumor have not yet been elucidated. Previously, we have synthesized a series of novel dithiocarbamate derivatives. These DTCs were examined for cytotoxic activities against five human cancer cell lines. In this study, one of dithiocarbamate (DTC1) with higher potential for HeLa cells was chosen to investigate molecular mechanisms for its anti-tumor activities. DTC1 could inhibit proliferation, and highly induce apoptosis in HeLa cells by activating caspase-3, -6 and -9; moreover, activities of caspase-3, -6 and -9 were inhibited by pan-caspase inhibitor, Z-VAD-FMK. Furthermore, DTC1 decreased the levels of Bcl-2 and Bcl-xL, and increased expression of cytosol cytochrome c, Bak, Bax and p53 in a time-dependent manner but had no effect on the level of Rb. It was shown that DTC1 induced HeLa cells apoptosis through a p53-dependent pathway as tested by the wild type p53 inhibitor, pifithrin-α. Additionally, the relative expression of E6 and E7 were evaluated in HPV18-positive (HeLa cells) by real-time PCR and western blotting. The results firstly demonstrated that DTC1 suppressed both expression of E6 mRNA and E6 oncoprotein, but had no effect on the expression of E7 mRNA and protein in HPV18. Our results suggested that DTC1 may serve as novel chemotherapeutic agents in the treatment of cervical cancer and potential anti-HPV virus candidates that merit further studies.

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Abbreviations

IC50 :

Half maximal inhibitory concentration

PI:

Propidium iodide

TLC:

Thin layer chromatography

DMSO:

Dimethyl sulfoxide

NMR:

Nuclear magnetic resonance

PBS:

Phosphate-buffered saline

BCA:

Bicinchoninic acid

SDS-PAGE:

Sodium dodecyl sulfate poly-acrylamide gel electrophoresis

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

MTT:

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

Caspase:

Cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases

PMSF:

Phenylmethylsufonyl fluoride

PVDF:

Poly-vinylidene difluoride

Rb:

Retinoblastoma

HPV:

Human papillomavirus

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Acknowledgments

This research was financially supported by Natural Science Foundation of Xinjiang Uygur Autonomous Region (No. 2011211B51) and Western Action Project of Bureau of Resources and Environmental Science, Chinese Academy of Sciences (KZCX-XB2-17), P. R. China.

Conflict of interest

The authors indicated no potential conflicts of interest.

Compliance with ethical standards

This research does not involve human participants and/or animals.

Author information

Author notes

  1. Yanhong Li

    Present address: Xinjiang Key Laboratory of Special Species Conservation and Regulatory Biology, College of Life Science, Xinjiang Normal University, Urumqi, 830054, China

  2. Hongxue Qi

    Present address: State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, 510640, China

Authors and Affiliations

  1. Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China

    Hongxue Qi, Xiaobo Li, Xueling Hou, Xueying Lu & Xiangwen Xiao

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  1. Yanhong Li
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  2. Hongxue Qi
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  3. Xiaobo Li
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  4. Xueling Hou
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  5. Xueying Lu
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  6. Xiangwen Xiao
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Corresponding author

Correspondence to Xiaobo Li.

Additional information

Yanhong Li and Hongxue Qi have contributed equally to this work.

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Li, Y., Qi, H., Li, X. et al. A novel dithiocarbamate derivative induces cell apoptosis through p53-dependent intrinsic pathway and suppresses the expression of the E6 oncogene of human papillomavirus 18 in HeLa cells. Apoptosis 20, 787–795 (2015). https://doi.org/10.1007/s10495-015-1114-4

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  • DOI: https://doi.org/10.1007/s10495-015-1114-4

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