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Extra-Hepatic Cancer Represses Hepatic Drug Metabolism Via Interleukin (IL)-6 Signalling

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Abstract

Purpose

In many cancer patients, the malignancy causes reduced hepatic drug clearance leading to potentially serious complications from the use of anticancer drugs. The mechanisms underlying this phenomenon are poorly understood. We aimed to identify tumor-associated inflammatory pathways that alter drug response and enhance chemotherapy-associated toxicity.

Methods

We studied inflammatory pathways involved in extra-hepatic tumor mediated repression of CYP3A, a major hepatic drug metabolizing cytochrome P450 subfamily, using a murine Engelbreth-Holm-Swarm sarcoma model. Studies in IL-6 knockout mice determined the source of elevated IL-6 in tumor-bearing animals and monoclonal antibodies against IL-6 were used to intervene in this inflammatory pathway.

Results

Our studies confirm elevated plasma IL-6 levels and reveal activation of Jak/Stat and Mapk signalling pathways and acute phase proteins in livers of tumor-bearing mice. Circulating IL-6 was predominantly produced by the tumor xenograft, rather than being host derived. Anti IL-6 antibody intervention partially reversed tumor-mediated inflammation and Cyp3a gene repression.

Conclusions

IL-6 is an important player in cancer-related repression of CYP3A-mediated drug metabolism and activation of the acute phase response. Targeting IL-6 in cancer patients may prove an effective approach to alleviating cancer-related phenomena, such as adverse drug-related outcomes commonly associated with cancer chemotherapy.

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Abbreviations

CRP:

C-reactive protein

CYP3A4:

Cytochrome P450 3A4

EHS:

Engelbreth-Holm-Swarm Sarcoma

ERK:

extracellular-signal-regulated kinases

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

gp130:

glycoprotein 130

IL-1β:

interleukin-1 beta

IL-6:

interleukin-6

JAK:

Janus kinase

Jnk:

c-Jun N-terminal kinases

MAPK:

mitogen-activated protein kinase

SAP:

serum amyloid P

SAPK:

stress-activated protein kinases

STAT:

signal transducers and activators of transcription

TNF-α:

tumor necrosis factor-alpha

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Acknowledgments and Disclosures

This work was supported by National Health and Medical Research Council of Australia Project Grants 352419 (GRR, SJC, CL) and 402493 (CL). The authors have no competing interests to disclose.

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Authors and Affiliations

  1. Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead, NSW, 2145, Australia

    Marina Kacevska, Rohini Sharma & Christopher Liddle

  2. Cancer Pharmacology Unit ANZAC Research Institute & Concord Hospital, University of Sydney, Concord, NSW, 2139, Australia

    Marina Kacevska, Andre Mahns, Stephen J. Clarke & Graham R. Robertson

  3. Department of Experimental Medicine, Imperial College, London, UK

    Rohini Sharma

  4. Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW, 2065, Australia

    Stephen J. Clarke

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  1. Marina Kacevska
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  2. Andre Mahns
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  3. Rohini Sharma
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  4. Stephen J. Clarke
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  5. Graham R. Robertson
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  6. Christopher Liddle
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Correspondence to Stephen J. Clarke.

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Kacevska, M., Mahns, A., Sharma, R. et al. Extra-Hepatic Cancer Represses Hepatic Drug Metabolism Via Interleukin (IL)-6 Signalling. Pharm Res 30, 2270–2278 (2013). https://doi.org/10.1007/s11095-013-1042-3

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  • DOI: https://doi.org/10.1007/s11095-013-1042-3

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