Revisiting Old Drugs as Novel Agents for Retinoblastoma: In Vitro and In Vivo Antitumor Activity of Cardenolides

Abstract

PURPOSE Intraarterial delivery of chemotherapeutic agents offers a new and exciting opportunity for the treatment of advanced intraocular retinoblastoma. It allows local delivery of relatively high doses of chemo agents while bypassing general blood circulation. For this reason we sought to revisit some of the FDA approved drugs for the treatment of retinoblastoma. METHODS High throughput screening (HTS) of 2,640 approved drugs and bioactive compounds resulted in the identification of cytotoxic agents with potent activity toward both the Y79 and RB355 human retinoblastoma cell lines. Subsequent profiling of the drug candidates was performed in a panel of ocular cancer cell lines. Induction of apoptosis in Y79 cells was assessed by immunofluorescence detection of activated Caspase-3. Therapeutic effect was evaluated in a xenograft model of retinoblastoma. RESULTS We have identified several FDA approved drugs with potent cytotoxic activity toward retinoblastoma cell lines in vitro. Among them were several cardiac glycosides, a class of cardenolides historically associated with the prevention and treatment of congestive heart failure. Caspase-3 activation studies provided an insight into the mechanism of action of cardenolides in retinoblastoma cells. When tested in a xenograft model of retinoblastoma, the cardenolide ouabain induced complete tumor regression in the treated mice. CONCLUSIONS We have identified cardenolides as a new class of antitumor agents for the treatment of retinoblastoma. We propose that members of this class of cardiotonic drugs could be repositioned for retinoblastoma if administered locally via direct intraarterial infusion.

Progress in Small Molecule Therapeutics for the Treatment of Retinoblastoma

“…While many studies have employed a xenograft model based on subcutaneous injection of cultured retinoblastoma cells to evaluate novel retinoblastoma therapeutics, [123–126] results from these studies are difficult to interpret as one of the primary challenges of treating retinal disease is reaching the intraocular target site. Thus, while these studies provide some proof-of-concept for the efficacy of a given compound, they do not address whether or not the compound is likely to work in the eye after systemic administration.…”

Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma

“…Complications observed in clinical trials have been serious and have included vitreous hemorrhage, microemboli to the retina and choroid, myositis, eyelid edema, orbital congestion with resulting dysmotility, choroidal atrophy, ophthalmic artery stenosis, and branch retinal artery occlusion, resulting in blindness (119,120). Although the long-term rate of tumor recurrence or progression to bilateral disease is currently unknown, other treatments delivered by this approach are also under investigation (121,122).…”

Finding Promiscuous Old Drugs for New Uses

“…The anti-cancer drug daunorubicin was active against neuroblastoma (10) and was an NF-kB inhibitor (11). The cardiac glycoside digoxin was active against retinoblastoma (12) and an inhibitor of hypoxia inducible factor (13). The progestrogen hydroxyprogesterone has antimalarial (9) and glucocorticoid receptor modulator activity.…”