Poly ADP Ribose Polymerase Inhibitor Olaparib Targeting Microhomology End Joining in Retinoblastoma Protein Defective Cancer: Analysis of the Retinoblastoma Cell-Killing Effects by Olaparib after Inducing Double-Strand Breaks.

Abstract

Retinoblastoma is the most common intraocular cancer in childhood. Loss of function in both copies of the RB1 gene is the causal mutation of retinoblastoma. Current treatment for retinoblastoma includes the use of chemotherapeutic agents, such as the DNA damaging agent etoposide, which is a topoisomerase II poison that mainly generates DNA double-strand breaks (DSBs) and genome instability. Unfaithful repairing of DSBs could lead to secondary cancers and serious side effects. Previously, we found that RB knocked-down mammalian cells depend on a highly mutagenic pathway, the micro-homology mediated end joining (MMEJ) pathway, to repair DSBs. Poly ADP ribose polymerase 1 (PARP1) is a major protein in promoting the MMEJ pathway. In this study, we explored the effects of olaparib, a PARP inhibitor, in killing retinoblastoma cells. Retinoblastoma cell line Y79 and primary retinoblastoma cells expressed the cone-rod homeobox protein (CRX), a photoreceptor-specific marker. No detectable RB expression was found in these cells. The co-treatment of olaparib and etoposide led to enhanced cell death in both the Y79 cells and the primary retinoblastoma cells. Our results demonstrated the killing effects in retinoblastoma cells by PARP inhibitor olaparib after inducing DNA double-strand breaks. The use of olaparib in combination with etoposide could improve the cell-killing effects. Thus, lower dosages of etoposide can be used to treat retinoblastoma, which would potentially lead to a lower level of DSBs and a relatively more stable genome.

• Authors: Yuning Jiang, Jason C Yam, Wai Kit Chu
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 19 (Oct 01 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34639028 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Retinoblastoma Protein
• Etoposide
• olaparib

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• DNA Breaks, Double-Stranded
• DNA End-Joining Repair (drug effects)
• Dose-Response Relationship, Drug
• Etoposide (pharmacology)
• Humans
• Phthalazines (pharmacology)
• Piperazines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Recombinational DNA Repair (drug effects)
• Retinoblastoma (genetics, metabolism)
• Retinoblastoma Protein (deficiency)