4-Hydroxybenzoic acid (4-HBA) enhances the sensitivity of human breast cancer cells to adriamycin as a specific HDAC6 inhibitor by promoting HIPK2/p53 pathway

Biochem Biophys Res Commun. 2018 Oct 12;504(4):812-819. doi: 10.1016/j.bbrc.2018.08.043. Epub 2018 Sep 11.

Abstract

Breast cancer is reported a very complex disease along with heterogeneous morphological characteristics and unrelated clinical behavior, and is a leading cancer among female. Nevertheless, chemo-resistance is frequently observed. Adriamycin (ADM) is a always employed drug to treat clinical breast cancer. However, strong resistance to ADM limited its clinical efficacy. Deregulation of HDAC6 activity is linked to various diseases including cancer resulting in accumulating interest for developing HDAC6 inhibitors. In the present study, for the first time, we found that 4-Hydroxybenzoic acid (4-HBA), as histone deacetylase 6 (HDAC6) inhibitor, could successfully reverse ADM resistance in human breast cancer cells. 4-HBA significantly promoted the anticancer effect of ADM on apoptosis induction, as evidenced by the increased expressions of Caspase-3 and PARP cleavage, which was associated with the promotion p53 and homeodomain interacting protein kinase-2 (HIPK2) expressions in ADM-resistant breast cancer cells. Furthermore, the suppressive effect of ADM on drug-resistant breast cancer cells was accelerated by 4-HBA through increasing the number of cells distributed in G2/M phase of cell cycle arrest. Inhibiting HIPK2/p53 pathway could abolish 4-HBA/ADM co-treatment-induced apoptosis and G2/M cell cycle arrest. Importantly, HDAC6 expressions were also significantly down-regulated in ADM-resistance breast cancer cells co-treated with ADM and 4-HBA. Additionally, 4-HBA clearly potentiated the anticancer role of ADM in the MCF-7 breast cancer animal model with low toxicity. Therefore, 4-HBA could be applied as an effective HDAC6 inhibitor to reverse human breast cancer resistance. Herein, the 4-HBA and ADM combination might represent as a useful therapeutic strategy to prevent human breast cancer.

Keywords: 4-Hydroxybenzoic acid; Adriamycin; Breast cancer; HDAC6; HIPK2/p53.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Carrier Proteins / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacology*
  • Female
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Mice, Inbred BALB C
  • Parabens / administration & dosage
  • Parabens / pharmacology*
  • Protein Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Carrier Proteins
  • Histone Deacetylase Inhibitors
  • Parabens
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Doxorubicin
  • HIPK2 protein, human
  • Protein Serine-Threonine Kinases
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • 4-hydroxybenzoic acid