A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

Int J Oncol. 2013 Oct;43(4):1080-6. doi: 10.3892/ijo.2013.2042. Epub 2013 Jul 30.


Renal cell carcinoma (RCC) is resistant to traditional cancer therapies such as radiation therapy and chemotherapy. The use of targeted therapies has improved the clinical outcomes of patients with metastatic RCC. However, most patients acquire resistance against targeted therapies over time. We report that the combination of the novel histone deacetylase (HDAC) inhibitor OBP-801, also known as YM753 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 synergistically inhibits cell growth and induces apoptosis in RCC cells. This combination activated caspase-3, -8 and -9 and the pan-caspase inhibitor zVAD-fmk significantly reduced the apoptotic response to the treatment with OBP-801 and LY294002. Moreover, the combined treatment induced intracellular reactive oxygen species (ROS) and the radical scavenger N-acetyl-L-cysteine (NAC) blocked the intracellular ROS and apoptosis induced by OBP-801 and LY294002. The co-treatment with OBP-801 and LY294002 markedly decreased survivin and the X-linked inhibitor of apoptosis protein (XIAP) protein levels, but Bcl-2 family members were not altered by the OBP-801/LY294002 co-treatment. These alterations were restored by NAC treatment. The transient transfection of survivin and XIAP reduced the apoptotic response to the OBP-801/LY294002 co-treatment. Additionally, OBP-801 was significantly more effective than SAHA, another HDAC inhibitor, in the combination with LY294002 against 786-O cells. Taken together, these results strongly suggest the combination of OBP-801 and LY294002 to be a promising treatment for RCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Inhibitor of Apoptosis Proteins / biosynthesis*
  • Inhibitor of Apoptosis Proteins / genetics
  • Morpholines / pharmacology
  • Peptides, Cyclic / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Reactive Oxygen Species / metabolism
  • Survivin
  • X-Linked Inhibitor of Apoptosis Protein / biosynthesis*
  • X-Linked Inhibitor of Apoptosis Protein / genetics


  • BIRC5 protein, human
  • Chromones
  • Enzyme Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Morpholines
  • Peptides, Cyclic
  • Phosphoinositide-3 Kinase Inhibitors
  • Reactive Oxygen Species
  • Survivin
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • YM753 compound
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Caspase 3