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Vinorelbine-Induced Oxidative Injury in Human Endothelial Cells Mediated by AMPK/PKC/NADPH/NF-κB Pathways

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Abstract

Vinorelbine tartrate (VNR), a semi-synthetic vinca alkaloid acquired from vinblastine, has extensively been used as an anticancer agent. However, VNR-induced oxidative damage may cause several side effects, such as venous irritation, vascular pain, and necrotizing vasculitis, thereby repressing clinical treatment efficiency. The molecular mechanisms underlying the induced oxidative stress in endothelial cells are still largely unknown. This study was designed to test the hypothesis that VNR induces oxidative injury through modulation of AMP-activated protein kinase (AMPK) and possible mechanisms were then explored. Human umbilical vein endothelial cells (HUVECs) were treated with VNR (5–0.625 μM) to produce oxidative damage. The VNR-mediated AMPK, PKC, and NADPH oxidase expressions were investigated by western blotting. Furthermore, several oxidative stress-induced oxidative damage markers as well as pro-inflammatory responses were also investigated. VNR treatment resulted in dephosphorylation of AMPK, which in turn led to an activation of NADPH oxidase by PKC; however, the phenomena were repressed by AICAR (an agonist of AMPK). Furthermore, VNR suppressed Akt/eNOS and enhanced p38 mitogen-activated protein kinase (MAPK), which in turn activated the NF-κB pathway. Furthermore, VNR facilitated several pro-inflammatory events, such as the adherence of monocytic THP-1 cells to HUVECs, pro-inflammatory cytokines release, and overexpression of adhesion molecular. Our results highlight a possible molecular mechanism for VNR-mediated endothelial dysfunction.

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Abbreviations

VNR:

Vinorelbine tartrate

ROS:

Reactive oxygen species

AMPK:

AMP-activated protein kinase

PKC:

Protein kinase C

MAPK:

Mitogen-activated protein kinase

DPI:

Diphenyleneiodonium

EDTA:

Ethylene diaminotetraacetic acid

VCAM-1:

Vascular cell adhesion molecule-1

ICAM-1:

Intercellular adhesion molecules

IL-8:

Interleukin-8

NO:

Nitric oxide

eNOS:

Endothelial NO synthase

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Acknowledgments

This study was supported by grants from the National Science Council, (NSC 98-2320-B-039-020-MY3, NSC 97-3111-B-075-001-MY3, 97-2320-B-075-003-MY3), China Medical University (CMU99-S-13), Taiwan, ROC. This study was supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004).

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Authors and Affiliations

  1. Department of Physical Therapy and Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan No. 91, Shuch-Shih Road, Taichung, 404, Taiwan

    Kun-Ling Tsai & Hsiu-Chung Ou

  2. Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan

    Tsan-Hung Chiu

  3. 3M Taiwan LTD. Health Care Business, Kaohsiung, Taiwan

    Mei-Hsueh Tsai

  4. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Hsiao-Yun Chen

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  1. Kun-Ling Tsai
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  4. Hsiao-Yun Chen
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  5. Hsiu-Chung Ou
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Correspondence to Hsiu-Chung Ou.

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Tsai, KL., Chiu, TH., Tsai, MH. et al. Vinorelbine-Induced Oxidative Injury in Human Endothelial Cells Mediated by AMPK/PKC/NADPH/NF-κB Pathways. Cell Biochem Biophys 62, 467–479 (2012). https://doi.org/10.1007/s12013-011-9333-y

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