Back to Search
Start Over
Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma.
- Source :
-
Oncology research [Oncol Res] 2021 Sep 07; Vol. 28 (7), pp. 745-761. Date of Electronic Publication: 2021 Feb 11. - Publication Year :
- 2021
-
Abstract
- Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors.
- Subjects :
- Animals
Antineoplastic Agents adverse effects
Apoptosis drug effects
Cell Cycle Checkpoints drug effects
Cell Cycle Proteins genetics
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Gene Expression Profiling methods
Glycine adverse effects
Glycine pharmacology
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Protein Serine-Threonine Kinases genetics
Proto-Oncogene Proteins genetics
Retinal Neoplasms genetics
Retinal Neoplasms pathology
Retinoblastoma genetics
Retinoblastoma pathology
Sulfones adverse effects
Xenograft Model Antitumor Assays
p38 Mitogen-Activated Protein Kinases metabolism
Polo-Like Kinase 1
Antineoplastic Agents pharmacology
Cell Cycle Proteins metabolism
Glycine analogs & derivatives
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins metabolism
Retinal Neoplasms drug therapy
Retinoblastoma drug therapy
Sulfones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1555-3906
- Volume :
- 28
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Oncology research
- Publication Type :
- Academic Journal
- Accession number :
- 33573708
- Full Text :
- https://doi.org/10.3727/096504021X16130322409507