Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents

PLoS One. 2015 Sep 30;10(9):e0139298. doi: 10.1371/journal.pone.0139298. eCollection 2015.

Abstract

Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Berberine / administration & dosage*
  • Berberine / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Coptis chinensis
  • Drugs, Chinese Herbal / administration & dosage*
  • Hormesis*
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasms / drug therapy*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / administration & dosage
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Stress, Physiological / drug effects

Substances

  • Antineoplastic Agents
  • Drugs, Chinese Herbal
  • Protein Kinase Inhibitors
  • Berberine
  • Coptidis rhizoma extract
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase Kinases

Grants and funding

This study was supported by the Macao Science and Technology Development Fund (code: 074/2013/A to CH) (http://www.fdct.gov.mo/) and the Research Fund of the University of Macau (code: MYRG107(Y1-L3)-ICMS13-HCW to CH, MYRG2015-00081-ICMS-QRCM to CH, and MRG013/HCW/2014/ICMS to CH) (www.umac.mo) in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Co-author Lidi Zou is employed by Institute of Chinese Materia Medica at China Academy of Chinese Medical Sciences, where provided support in the form of salary for author LZ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.