Inhibition of retinoblastoma cell growth by CEP1347 through ctivation of the P53 pathway

Abstract

Background/Aim: Despite advances in treatment modalities, the visual prognosis of retinoblastoma still remains unsatisfactory, underscoring the need to develop novel therapeutic approaches. Materials and Methods: The effect on the growth of six human retinoblastoma cell lines and a normal human fibroblast cell line of CEP1347, a small-molecule kinase inhibitor originally developed for the treatment of Parkinson’s disease and therefore with a known safety profile in humans, was examined. The role of the P53 pathway in CEP1347-induced growth inhibition was also investigated. Results: CEP1347 selectively inhibited the growth of retinoblastoma cell lines expressing murine double minute 4 (MDM4), a P53 inhibitor. Furthermore, CEP1347 reduced the expression of MDM4 and activated the P53 pathway in MDM4-expressing retinoblastoma cells, which was required for the inhibition of their growth by CEP1347. Conclusion: We propose CEP1347 as a promising candidate for the treatment of retinoblastomas, where functional inactivation of P53 as a result of MDM4 activation is reportedly common. Although retinoblastoma is a rare form of cancer, it is one of the most common malignant intraocular tumors in children and affects one in 15,000-20,000 individuals worldwide (1, 2). Although it can be life-threatening if left untreated, the survival rate in developed countries is over 95% due to the availability of numerous treatment strategies that are effective for specific disease stages. These treatments include local