Acetylcarnitine potentiates the anticarcinogenic effects of butyrate on SW480 colon cancer cells

Int J Oncol. 2015 Aug;47(2):755-63. doi: 10.3892/ijo.2015.3029. Epub 2015 Jun 4.

Abstract

Butyrate is a potent anticarcinogenic compound against colon cancer cells in vitro. However, its rapid metabolism is hypothesized to limit its anticancer benefits in colonic epithelial cells. Carnitine, a potent antioxidant, is essential to fatty acid oxidation. The aims of this study were to identify a colon cancer cell line capable of transporting carnitine. We evaluated the effect of carnitine and acetylcarnitine (ALCAR) on the response of colon carcinoma cells to butyrate. We explored the mechanisms underlying the anticarcinogenic benefit. SW480 cells were incubated with butyrate ± carnitine or ALCAR. Carnitine uptake was assessed using [3H]-carnitine. Apoptosis and cell viability were assessed using an ELISA kit and flow cytometry, respectively. Modulation of proteins implicated in carnitine transport, cell death and proliferation were assessed by western blotting. SW480 cells were found to transport carnitine primarily via the OCTN2 transporter. Butyrate induced SW480 cell death occurred at concentrations of 2 mM and higher. Cells treated with the combination of butyrate (3 mM) with ALCAR exhibited increased mortality. The addition of carnitine or ALCAR also increased butyrate-induced apoptosis. Butyrate increased levels of cyclin D1, p21 and PARP p86, but decreased Bcl-XL and survivin levels. Butyrate also downregulated dephospho-β-catenin and increased acetylated histone H4 levels. Butyrate and carnitine decreased survivin levels by ≥25%. ALCAR independently induced a 20% decrease in p21. These results demonstrate that butyrate and ALCAR are potentially beneficial anticarcinogenic nutrients that inhibit colon cancer cell survival in vitro. The combination of both agents may have superior anticarcinogenic properties than butyrate alone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcarnitine / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols
  • Butyrates / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Colonic Neoplasms / drug therapy*
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Organic Cation Transport Proteins / metabolism
  • Solute Carrier Family 22 Member 5

Substances

  • Antineoplastic Agents
  • Butyrates
  • Organic Cation Transport Proteins
  • SLC22A5 protein, human
  • Solute Carrier Family 22 Member 5
  • Acetylcarnitine