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Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production

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Abstract

Drug resistance remains a major hurdle to successful cancer treatment. Many mechanisms such as overexpression of multidrug-resistance related proteins, increased drug metabolism, decreased apoptosis, and impairment of signal transduction pathway can contribute multidrug resistance (MDR). Recent studies strongly suggest a close link between cytokines and drug resistance. To identify new targets involved in drug resistance, we established a multidrug-resistant human breast cancer cell line MCF-7/R and examined the cytokine profile using cytokine antibody array technology. Among 120 cytokines/chemokines screened, IL-6, IL-8, and 13 other proteins were found to be markedly increased in drug-resistant MCF-7/R cell line as compared to sensitive MCF-7/S cell line, while 7 proteins were specifically reduced in drug-resistant MCF-7/R cells. Neutralizing antibodies against IL-6 and IL-8 partially reversed the drug resistance of MCF-7/R to paclitaxel and doxorubicin, while a neutralizing antibody against MCP-1 had no significant effect. Inhibition of endogenous IL-6 or IL-8 by siRNA technology significantly enhanced drug sensitivity of MCF-7/R cells. Furthermore, overexpression of IL-6 or IL-8 expression by transfection increased the ADM resistance in MCF-7/S cells. Our data suggest that increased expression levels of IL-6 and IL-8 may contribute to MDR in human breast cancer cells.

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Abbreviations

ADM:

Doxorubicin

BSA:

Bovine serum albumin

ECL:

Enhanced chemiluminescence

ELISA:

Enzyme-linked immunosorbent assays

P-gp:

P-glycoprotein

HRP:

Horseradish peroxidase

IL:

Interleukin

MCP-1:

Monocyte chemotactic protein-1

MDR:

Multidrug resistance

MRP:

Multidrug resistance protein

PVDF:

Polyvinylidene difluoride

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Acknowledgments

We would like to express our thanks for the support of the leading scientist project for Guangzhou economic development district (2009L-P180), Guangzhou leading talent entrepreneurial venture (LCY201111), Guangdong innovative research and development team (201001s0104659419), research grants from the Guangzhou economic development district (2010Q-P450) and partially support from National Institute of Health (No. 1R15CA143701). We also greatly appreciate Dr. Valerie Jones’s comments on the manuscript.

Conflict of interest

Zhi Shi, Ruo-Pan Huang: employed by RayBiotech, Inc, China and South China Biochip Research Center, China; Jin Zhu, Ruo-Chun Huang, Ruo-Pan Huang: employed by RayBiotech, Inc, USA; Wei-Min Yang, Li-Pai Chen, Dong-Hua Yang, Qi Zhou, Jun-Jiang Chen, Zhe-Sheng Chen: no disclosures.

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Authors and Affiliations

  1. RayBiotech, Inc, Guangzhou, China

    Zhi Shi & Ruo-Pan Huang

  2. South China Biochip Research Center, Guangzhou, China

    Zhi Shi & Ruo-Pan Huang

  3. Department of Gynaecology, Wuxi Maternal and Child Health Hospital, Wuxi, China

    Wei-Min Yang

  4. Department of Gynaecologic Oncology, Cancer Institute and Hospital, Guangzhou Medical University, Guangzhou, China

    Li-Pai Chen

  5. Biosample Repository, Fox Chase Cancer Center, Philadelphia, PA, USA

    Dong-Hua Yang

  6. Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Qi Zhou

  7. RayBiotech, Inc, 3067 Parkway Lane, Norcross, GA, 30092, USA

    Jin Zhu, Ruo-Chun Huang & Ruo-Pan Huang

  8. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John’s University, Queens, NY, USA

    Jun-Jiang Chen & Zhe-Sheng Chen

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  1. Zhi Shi
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Correspondence to Ruo-Pan Huang.

Additional information

Zhi Shi, Wei-Min Yang, and Li-Pai Chen contributed equally to this study.

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Shi, Z., Yang, WM., Chen, LP. et al. Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production. Breast Cancer Res Treat 135, 737–747 (2012). https://doi.org/10.1007/s10549-012-2196-0

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  • DOI: https://doi.org/10.1007/s10549-012-2196-0

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