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Inhibition of AMP-activated protein kinase pathway sensitizes human leukemia K562 cells to nontoxic concentration of doxorubicin

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Abstract

Doxorubicin (Dox) is a commonly used anthracycline in many antitumor regimens. The dose related Dox-induced cardiotoxicity often poses challenge in clinical practice, lowering its dose and administering it in combination with other compound is an option. In this study, we found that a nontoxic concentration of Dox at 34.5 nM (20 ng/ml) combined with Compound C, an inhibitor used in AMP-activated protein kinase (AMPK) pathway, could kill human leukemia K562 cells. Additionally, this study confirmed that the combined effect was related to the inhibition of some key proteins such as AMPK and acetyl CoA carboxylase. Moreover, down-regulation of these key proteins in AMPK pathway using siRNA technology also sensitized K562 cells to nontoxic concentration of Dox. The study also showed that Dox at a concentration of 345.0 nM (200 ng/ml) or 862.0 nM (500 ng/ml) that is lower than a typical value of 1–2 μM Dox in patients could kill human leukemia K562 cells. Taken together, our results suggest that inhibition of AMPK pathway by Compound C or siRNA sensitizes K562 cells to nontoxic concentration of Dox which is much lower than typical concentration in plasma of clinical patients.

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Abbreviations

AMPK:

AMP-activated protein kinase

ACC:

Acetyl CoA carboxylase

FBS:

Fetal bovine serum

Dox:

Doxorubicin

MTT:

Thiazolyl blue tetrazolium bromide

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Acknowledgments

This work was partly supported by the Science and Technology Development Fund from Nanjing Medical University (No. 08NMUZ025) and National Natural Science Foundation of China (30971170). We thank Dr. K. Y. Williams (Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294) for carefully reading, proof-reading, and editing this manuscript for its language and content.

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Authors and Affiliations

  1. Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, People’s Republic of China

    Qun Zhu

  2. Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, 210009, Jiangsu, People’s Republic of China

    Bo Shen

  3. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Boshao Zhang

  4. Department of Pathophysiology, Medical School of Southeast University, Nanjing, 210009, Jiangsu, People’s Republic of China

    Wei Zhang

  5. Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA

    Steve H. Chin

  6. Research Center of Life Science, University of South China, 28# West Changsheng Road, Hengyang, 421001, Hunan, People’s Republic of China

    Junfei Jin & Duan-fang Liao

  7. Department of Traditional Chinese Diagnotics, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, People’s Republic of China

    Junfei Jin & Duan-fang Liao

Authors
  1. Qun Zhu
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  2. Bo Shen
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  3. Boshao Zhang
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  4. Wei Zhang
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  5. Steve H. Chin
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  6. Junfei Jin
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  7. Duan-fang Liao
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Corresponding authors

Correspondence to Junfei Jin or Duan-fang Liao.

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Qun Zhu and Bo Shen authors contributed equally to this work.

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Zhu, Q., Shen, B., Zhang, B. et al. Inhibition of AMP-activated protein kinase pathway sensitizes human leukemia K562 cells to nontoxic concentration of doxorubicin. Mol Cell Biochem 340, 275–281 (2010). https://doi.org/10.1007/s11010-010-0428-3

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  • DOI: https://doi.org/10.1007/s11010-010-0428-3

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