Caffeic acid derivatives inhibit the growth of colon cancer: involvement of the PI3-K/Akt and AMPK signaling pathways

PLoS One. 2014 Jun 24;9(6):e99631. doi: 10.1371/journal.pone.0099631. eCollection 2014.

Abstract

Background: The aberrant regulation of phosphatidylinositide 3-kinases (PI3-K)/Akt, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (m-TOR) signaling pathways in cancer has prompted significant interest in the suppression of these pathways to treat cancer. Caffeic acid (CA) has been reported to possess important anti-inflammatory actions. However, the molecular mechanisms by which CA derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid phenylpropyl ester (CAPPE), exert inhibitory effects on the proliferation of human colorectal cancer (CRC) cells have yet to be elucidated.

Methodology/principal findings: CAPE and CAPPE were evaluated for their ability to modulate these signaling pathways and suppress the proliferation of CRC cells both in vitro and in vivo. Anti-cancer effects of these CA derivatives were measured by using proliferation assays, cell cycle analysis, western blotting assay, reporter gene assay and immunohistochemical (IHC) staining assays both in vitro and in vivo. This study demonstrates that CAPE and CAPPE exhibit a dose-dependent inhibition of proliferation and survival of CRC cells through the induction of G0/G1 cell cycle arrest and augmentation of apoptotic pathways. Consumption of CAPE and CAPPE significantly inhibited the growth of colorectal tumors in a mouse xenograft model. The mechanisms of action included a modulation of PI3-K/Akt, AMPK and m-TOR signaling cascades both in vitro and in vivo. In conclusion, the results demonstrate novel anti-cancer mechanisms of CA derivatives against the growth of human CRC cells.

Conclusions: CA derivatives are potent anti-cancer agents that augment AMPK activation and promote apoptosis in human CRC cells. The structure of CA derivatives can be used for the rational design of novel inhibitors that target human CRC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Caffeic Acids / pharmacology*
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / pathology
  • HCT116 Cells
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Phenylethyl Alcohol / analogs & derivatives
  • Phenylethyl Alcohol / pharmacology

Substances

  • 3-phenylpropyl caffeate
  • Antineoplastic Agents
  • Caffeic Acids
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol

Grants and funding

This material is based upon work supported, in part, by the Ministry of Education, Taiwan, R.O.C. under the ATU plan, National Science Council grant, under Agreements NSC-100-2320-B-039-003, 100-2628-B005-002-MY4, 101-2320-B-039-054-MY3, 101-2320-B-005-006-MY3, 102-2911-I-005 -301, 101-2811-B-039-024, the Department of Health Grant under Agreements DOH 102-TD-B-111-004 and DOH-102-TD-C-111-005 and China Medical University (CMU) grant under Agreements CMU101- Award -10, CMU100-ASIA-11, CMU101-ASIA-3, and CMU101-S-25. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the Ministry of Education, National Science Council, Department of Health, National Chung Hsing University, Taipei Medical University, Asia University, University of California Davis and China Medical University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.