Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, enhances radiosensitivity and suppresses lung metastasis in breast cancer in vitro and in vivo

PLoS One. 2013 Oct 10;8(10):e76340. doi: 10.1371/journal.pone.0076340. eCollection 2013.

Abstract

Triple-negative breast cancer (TNBC), defined by the absence of an estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, is associated with an early recurrence of disease and poor outcome. Furthermore, the majority of deaths in breast cancer patients are from metastases instead of from primary tumors. In this study, MCF-7 (an estrogen receptor-positive human breast cancer cell line), MDA-MB-231 (a human TNBC cell line) and 4T1 (a mouse TNBC cell line) were used to investigate the anti-cancer effects of ionizing radiation (IR) combined with suberoylanilide hydroxamic acid (SAHA, an inhibitor of histone deacetylase (HDAC)) and to determine the underlying mechanisms of these effects in vitro and in vivo. We also evaluated the ability of SAHA to inhibit the metastasis of 4T1 cells. We found that IR combined with SAHA showed increased therapeutic efficacy when compared with either treatment alone in MCF-7, MDA-MB-231 and 4T1 cells. Moreover, the combined treatment enhanced DNA damage through the inhibition of DNA repair proteins. The combined treatment was induced primarily through autophagy and ER stress. In an orthotopic breast cancer mouse model, the combination treatment showed a greater inhibition of tumor growth. In addition, SAHA inhibited the migration and invasion abilities of 4T1 cells and inhibited breast cancer cell migration by inhibiting the activity of MMP-9. In an in vivo experimental metastasis mouse model, SAHA significantly inhibited lung metastasis. SAHA not only enhances radiosensitivity but also suppresses lung metastasis in breast cancer. These novel findings suggest that SAHA alone or combined with IR could serve as a potential therapeutic strategy for breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Autophagy / drug effects
  • Autophagy / radiation effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Breast Neoplasms / radiotherapy
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / radiation effects
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Combined Modality Therapy
  • DNA Damage
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / radiation effects
  • Female
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors / therapeutic use
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Hydroxamic Acids / therapeutic use
  • Lung Neoplasms / secondary*
  • Mice
  • Neoplasm Invasiveness
  • Radiation Tolerance / drug effects*
  • Survival Analysis
  • Vorinostat
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Vorinostat
  • Histone Deacetylases

Grant support

This study was supported by the National Science Council, Taiwan (NSC101-2314-B-006-050 and NSC100-2325-B-400-012) and the Sinlau Christian Hospital, Tainan, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.