Panobinostat induces apoptosis via production of reactive oxygen species and synergizes with topoisomerase inhibitors in cervical cancer cells

Biomed Pharmacother. 2016 Dec:84:1393-1405. doi: 10.1016/j.biopha.2016.10.057. Epub 2016 Oct 29.

Abstract

Cervical cancer is the fourth major cause of cancer-related deaths in women worldwide and is the most common cancer in developing countries. Therefore, a search for novel treatment modalities is warranted. The present study is designed to investigate the effect of pan histone deacetylase inhibitor, 'panobinostat', on cervical cancer cells alone and in combination with topoisomerase inhibitors. We assessed the effect of panobinostat on two cervical cancer cell lines, HeLa and SiHa, for cell viability, apoptosis, oxidative stress and mitochondrial function using various assays. The results indicate that panobinostat reduces the viability of cervical cancer cells in a dose- and time-dependent manner; it arrests HeLa cells in G0/G1 and SiHa cells in G2/M phase of the cell cycle. Panobinostat induced apoptosis through an increase in the ROS production and the disruption of mitochondrial membrane potential. Concomitantly the expression of anti-apoptotic gene Bcl-xL was reduced, while levels of CDK inhibitor p21 and caspase-9 were increased. Panobinostat increased the acetylation of histone H3 indicating HDAC inhibition. In addition, panobinostat also showed synergistic effect with topoisomerase inhibitors mediated by increased activation of caspase-3/7 activity compared to that in cells treated with panobinostat alone. These results suggest a combination therapy using inhibitors of histone deacetylase and topoisomerase together could hold the promise for an effective targeted therapeutic strategy.

Keywords: Cervical cancer; Panobinostat; ROS generation; Synergistic effects; Topoisomerase inhibitors.

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • HeLa Cells
  • Histone Deacetylase Inhibitors / administration & dosage
  • Humans
  • Hydroxamic Acids / administration & dosage*
  • Indoles / administration & dosage*
  • Panobinostat
  • Reactive Oxygen Species / metabolism*
  • Topoisomerase Inhibitors / administration & dosage*
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / metabolism*

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Reactive Oxygen Species
  • Topoisomerase Inhibitors
  • Panobinostat