Open Access
ARTICLE
Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma
Huan Ma1, Cong Nie1, Ying Chen, Jinmiao Li, Yanjie Xie, Zhixin Tang, Yang Gao, Siming Ai,
Yuxiang Mao, Qian Sun, Rong Lu
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P.R. China
Oncology Research 2020, 28(7-8), 745-761. https://doi.org/10.3727/096504021X16130322409507
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.
Keywords
Cite This Article
Ma, H., Nie, C., Chen, Y., Li, J., Xie, Y. et al. (2020). Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma.
Oncology Research, 28(7-8), 745–761. https://doi.org/10.3727/096504021X16130322409507