Sequential combination therapy of ovarian cancer with cisplatin and γ-secretase inhibitor MK-0752

Gynecol Oncol. 2016 Mar;140(3):537-44. doi: 10.1016/j.ygyno.2015.12.011. Epub 2015 Dec 15.

Abstract

Objective: Ovarian cancer is one of the most lethal of women cancers and lack potent therapeutic options. There have many evidences demonstrate the Notch signaling has deregulation in variety of human malignancies.MK-0752 is a novel potent γ-secretase inhibitor and now assessed in clinical trial for treatment of several types of cancer, our objective was to investigate the anticancer effects and mechanisms of MK-0752 alone or combined with cisplatin in ovarian cancer.

Methods: Cell lines used: A2780, OVCAR3, SKOV3, HO8910PM, the effects of MK-0752 and cisplatin on cell proliferation were measured by MTT assay. The effect of combination treatment was examined by isobologram analysis. The distribution of cell cycle and cell apoptosis were analyzed using PI and Annexin V-FITC/PI staining by flow cytometric analysis. The mechanism in biochemistry was analyzed by using Western blot. Mouse xenograft model of A2780 was established to observe the anti-ovarian cancer effects in vivo setting, nude mice were randomized into four groups (n=6 per group) and treated every 4 days with control (solvent) group, MK-0752(25mg/kg) group, cisplatin (2mg/kg)group, combination group (both of MK-0752 and cisplatin).

Results: MK-0752 alone actively induced cell growth inhibition, G2/M phase cell cycle arrest and apoptosis with down-regulation of Notch1 and its downstream effectors including Hes1, XIAP, c-Myc and MDM2 in a dose- and time-dependent manner. Moreover, sequential combination of cisplatin prior to MK-0752 significantly promoted cell apoptosis and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice.

Conclusion: Our data supports the sequential combination of cisplatin prior to MK-0752 is a highly promising novel experimental therapeutic strategy against ovarian cancer.

Keywords: Cisplatin; Combination therapy; MK-0752; Ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Benzene Derivatives / administration & dosage
  • Benzene Derivatives / therapeutic use*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / administration & dosage
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Drug Synergism
  • Female
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy*
  • Propionates / administration & dosage
  • Propionates / therapeutic use*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptor, Notch1 / metabolism
  • Sulfones / administration & dosage
  • Sulfones / therapeutic use*
  • Transcription Factor HES-1
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • 3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid
  • Basic Helix-Loop-Helix Transcription Factors
  • Benzene Derivatives
  • Homeodomain Proteins
  • NOTCH1 protein, human
  • Propionates
  • Proto-Oncogene Proteins c-myc
  • Receptor, Notch1
  • Sulfones
  • Transcription Factor HES-1
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • HES1 protein, human
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Amyloid Precursor Protein Secretases
  • Cisplatin