Targeting Survivin Enhances Chemosensitivity in Retinoblastoma Cells and Orthotopic Tumors.

Angela Ferrario,Jonathan Kim,Natalie Rucker,Ariel Lederman,Charles Gomer,Sam Wong,Marian Luna

doi:10.1371/journal.pone.0153011

Angela Ferrario, Jonathan Kim + Show 5 more

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Treatments for retinoblastoma (Rb) vary depending on the size and location of the intraocular lesions and include chemotherapy and radiation therapy. We examined whether agents used to treat Rb induce a pro-survival phenotype associated with increased expression of survivin, a member of the inhibitor of apoptosis family of proteins. We document that exposure to carboplatin, topotecan or radiation resulted in elevated expression of survivin in two human Rb cell lines but not in normal retinal pigmented epithelial (RPE) cells. Cellular levels of survivin were attenuated in Rb cells exposed to an imidazolium-based survivin suppressant, Sepantronium bromide (YM155). Protein expression patterns of survivin in RPE cells were not altered following treatment protocols involving exposure to YM155. Including YM155 with chemotherapy or radiation increased levels of apoptosis in Rb cells but not in RPE cells. Intraocular luciferase expressing Rb tumors were generated from the Rb cell lines and used to evaluate the effects of carboplatin and YM155 on in-vivo survivin expression and tumor growth. Carboplatin induced expression of survivin while carboplatin combined with YM155 reduced survivin expression in tumor bearing eyes. The combination protocol was also most effective in reducing the rate of tumor regrowth. These results indicate that targeted inhibition of the anti-apoptotic protein survivin provides a therapeutic advantage for Rb cells and tumors treated with chemotherapy.

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Retinoblastoma (Rb) is the most common pediatric intraocular malignancy with an incidence of approximately 1 in 17,000 births [1]
Basal levels of survivin and x-linked inhibitor of apoptosis (XIAP) were detectable in non-treated cells while exposure to carboplatin (5 μM), topotecan (10 nM), or radiation (5 Gy) only induced increased survivin expression
We examined the effects of carboplatin, topotecan and radiation on ocular retinal pigmented epithelial (RPE) cells

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Introduction

Retinoblastoma (Rb) is the most common pediatric intraocular malignancy with an incidence of approximately 1 in 17,000 births [1]. The heritable form of Rb accounts for 40% of all cases, usually occurs during the first year of life, and most often presents as bilateral disease. The sporadic form of the disease accounts for the remaining 60% of cases, normally occurs between. Targeting Survivin for Retinoblastoma Treatment ages 2 and 5, and usually presents in only one eye [1,2,3]. Treatments for Rb depend on the size and location of the lesions and include local ablative procedures for small lesions and chemotherapeutic protocols for advanced disease [2]. There is an increased risk of secondary tumors following radiation in patients with the hereditary form of Rb [3]. The overall survival of Rb patients and the tumor responsiveness of current treatments are excellent. Tumor recurrences frequently lead to enucleations and there are ongoing concerns regarding both short and long term side effects from current therapies [6,7,8,9,10,11]

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