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

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,...

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Bibliographic Details
Published in:	Nanomedicine Vol. 14; no. 4; pp. 1395 - 1405
Main Authors:	Schumann, Canan, Chan, Stephanie, Millar, Jess A., Bortnyak, Yuliya, Carey, Katherine, Fedchyk, Alex, Wong, Leon, Korzun, Tetiana, Moses, Abraham S., Lorenz, Anna, Shea, Delany, Taratula, Olena, Khalimonchuk, Oleh, Taratula, Oleh
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-06-2018
Subjects:	Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - therapeutic use Apoptosis - drug effects Cell Line, Tumor cisplatin Cisplatin - administration & dosage Cisplatin - therapeutic use combinatorial therapy DJ-1 Female Humans Mice Mice, Nude ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Protein Deglycase DJ-1 - genetics Protein Deglycase DJ-1 - metabolism RNA, Small Interfering - genetics siRNA PBS IV chemotherapy ovarian cancer CI PTEN DJ-1 siRNA IP chemotherapy MAL-PEG-NHS NRS p53 LRT LHRH SD combinatorial therapy p-Akt PEG NRF2 ROS ES-2-luc PPIG4 qPCR cisplatin
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Summary:	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. We have developed and validated combinatorial treatment for metastatic ovarian cancer which consists of two monotherapies administered sequentially via intraperitoneal route for three cycles: (1) siRNA-loaded nanoparticles aimed to suppress DJ-1 protein, and (2) the chemotherapy agent, cisplatin. DJ-1 suppression by siRNA can simultaneously interfere with the expression of multiple oncogenic proteins responsible for ovarian cancer cells survival, migration, proliferation and resistance to platinum-based drugs. The developed therapy eradicated metastatic ovarian cancer tumors from the mice, and there was no cancer recurrence detected during the duration of the study. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Both authors contributed equally to this work
ISSN:	1549-9634 1549-9642
DOI:	10.1016/j.nano.2018.03.005