1. Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer cells and patient-derived xenograft mouse models
- Author
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Tu, Mei-Juan, Ho, Pui Yan, Zhang, Qian-Yu, Jian, Chao, Qiu, Jing-Xin, Kim, Edward J, Bold, Richard J, Gonzalez, Frank J, Bi, Huichang, and Yu, Ai-Ming
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Cancer ,Digestive Diseases ,Pancreatic Cancer ,Rare Diseases ,Biotechnology ,Genetics ,6.1 Pharmaceuticals ,5.1 Pharmaceuticals ,Albumins ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Cell Cycle Checkpoints ,Cell Line ,Tumor ,Cell Proliferation ,DNA-Binding Proteins ,Deoxycytidine ,Dose-Response Relationship ,Drug ,Female ,Gene Expression Regulation ,Neoplastic ,Humans ,Mice ,Inbred NOD ,Mice ,Nude ,Mice ,SCID ,Mice ,Transgenic ,MicroRNAs ,Paclitaxel ,Pancreatic Neoplasms ,Prodrugs ,Signal Transduction ,Tumor Burden ,Xenograft Model Antitumor Assays ,Gemcitabine ,miR-1291 ,Pancreatic cancer ,PDX model ,ARID3B ,Gemcitabine plus nab-paclitaxel ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Our recent studies have revealed that microRNA-1291 (miR-1291) is downregulated in pancreatic cancer (PC) specimens and restoration of miR-1291 inhibits tumorigenesis of PC cells. This study is to assess the efficacy and underlying mechanism of our bioengineered miR-1291 prodrug monotherapy and combined treatment with chemotherapy. AT-rich interacting domain protein 3B (ARID3B) was verified as a new target for miR-1291, and miR-1291 prodrug was processed to mature miR-1291 in PC cells which surprisingly upregulated ARID3B mRNA and protein levels. Co-administration of miR-1291 with gemcitabine plus nab-paclitaxel (Gem-nP) largely increased the levels of apoptosis, DNA damage and mitotic arrest in PC cells, compared to mono-drug treatment. Consequently, miR-1291 prodrug improved cell sensitivity to Gem-nP. Furthermore, systemic administration of in vivo-jetPEI-formulated miR-1291 prodrug suppressed tumor growth in both PANC-1 xenograft and PC patients derived xenograft (PDX) mouse models to comparable degrees as Gem-nP alone, while combination treatment reduced tumor growth more ubiquitously and to the greatest degrees (70-90%), compared to monotherapy. All treatments were well tolerated in mice. In conclusion, biologic miR-1291 prodrug has therapeutic potential as a monotherapy for PC, and a sensitizing agent to chemotherapy.
- Published
- 2019