Intraperitoneal nanotherapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin

Nanomedicine. 2018 Jun;14(4):1395-1405. doi: 10.1016/j.nano.2018.03.005. Epub 2018 Apr 7.

Abstract

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth and increasing survival of mice with metastatic ovarian cancer. Finally, three cycles of siRNA-mediated DJ-1 therapy in combination with a low dose of cisplatin completely eradicated ovarian cancer tumors from the mice, and there was no cancer recurrence detected for the duration of the study, which lasted 35 weeks.

Keywords: DJ-1; cisplatin; combinatorial therapy; ovarian cancer; siRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • Cisplatin / therapeutic use*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Protein Deglycase DJ-1 / genetics
  • Protein Deglycase DJ-1 / metabolism*
  • RNA, Small Interfering / genetics*

Substances

  • Antineoplastic Agents
  • RNA, Small Interfering
  • Protein Deglycase DJ-1
  • Cisplatin