Doxycycline Promotes Carcinogenesis & Metastasis via Chronic Inflammatory Pathway: An In Vivo Approach

PLoS One. 2016 Mar 21;11(3):e0151539. doi: 10.1371/journal.pone.0151539. eCollection 2016.

Abstract

Background: Doxycycline (DOX) exhibits anti-inflammatory, anti-tumor, and pro-apoptotic activity and is being tested in clinical trials as a chemotherapeutic agent for several cancers, including colon cancer.

Materials & methods: In the current study, the chemotherapeutic activity of doxycycline was tested in a rat model of colon carcinogenesis, induced by colon specific cancer promoter, 1,2, dimethylhydrazine (DMH) as well as study the effect of DOX-alone on a separate group of rats.

Results: Doxycycline administration in DMH-treated rats (DMH-DOX) unexpectedly increased tumor multiplicity, stimulated progression of colonic tumor growth from adenomas to carcinomas and revealed metastasis in small intestine as determined by macroscopic and histopathological analysis. DOX-alone treatment showed markedly enhanced chronic inflammation and reactive hyperplasia, which was dependent upon the dose of doxycycline administered. Moreover, immunohistochemical analysis revealed evidence of inflammation and anti-apoptotic action of DOX by deregulation of various biomarkers.

Conclusion: These results suggest that doxycycline caused chronic inflammation in colon, small intestine injury, enhanced the efficacy of DMH in tumor progression and provided a mechanistic link between doxycycline-induced chronic inflammation and tumorigenesis. Ongoing studies thus may need to focus on the molecular mechanisms of doxycycline action, which lead to its inflammatory and tumorigenic effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dimethylhydrazine
  • Animals
  • Body Weight / drug effects
  • Carcinogenesis / chemically induced*
  • Carcinogenesis / pathology
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Proliferation / drug effects
  • Chronic Disease
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / pathology
  • Cytochromes c / metabolism
  • Down-Regulation / drug effects
  • Doxycycline / adverse effects*
  • Immunohistochemistry
  • Inflammation / pathology*
  • Intestine, Small / drug effects
  • Intestine, Small / pathology
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • NF-kappa B / metabolism
  • Neoplasm Metastasis / pathology*
  • Rats, Sprague-Dawley
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • NF-kappa B
  • Tumor Suppressor Protein p53
  • Vascular Endothelial Growth Factor A
  • Cytochromes c
  • Caspase 3
  • Caspase 9
  • Matrix Metalloproteinase 9
  • 1,2-Dimethylhydrazine
  • Doxycycline

Grants and funding

The authors would like to thank Indian Council of Medical Research (ICMR), New Delhi, India, (Reference No- 3/1/3/JRF-2009/MPD-74) for financial support to the research work. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.