Abstract
Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor. High-risk NB is difficult to treat due to the lack of response to current therapies and aggressive disease progression. Despite novel drugs, alternative treatments and multi-modal treatments, finding an effective treatment strategy for these patients continues to be a major challenge. The current study focuses on examining the effects of FTY-720 or fingolimod, a drug that is FDA-approved for refractory multiple sclerosis, in NB. The results showed that FTY-720 regulates multiple pathways that result in various effects on calcium signaling, ion channel activation and cell survival/death pathways. FTY-720 rapidly inhibits TRPM7 channel activity, and inhibited TRPM7 kinase activity, modulates calcium signaling, induces a loss of mitochondrial membrane potential and opening of the mitochondrial permeability transition pore, and ultimately leads to cell death. Interestingly, the data also showed that low concentrations of FTY-720 sensitized drug-resistant NB cells to antineoplastic drugs. These results suggest that FTY-720 may be an attractive alternative for the treatment of NB.
Highlights
Neuroblastoma (NB) is the most common extracranial pediatric solid tumor
The current study focuses on examining the effects of FTY720 or fingolimod, a drug that is FDA-approved for refractory multiple sclerosis, in NB
The results showed that FTY-720 regulates multiple pathways that result in various effects on calcium signaling, ion channel activation and cell survival/death pathways
Summary
Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. NB is highly heterogeneous, with clinical outcomes that range from spontaneous regression to the development of multi-drug resistance. High-risk NB (~40–50% of patients) signifies poor prognosis, and is difficult to treat due to the lack of response to current therapies and aggressive disease progression [1,2,3]. Numerous studies have examined the effects of novel drugs, alternative treatments and multimodal treatments for patients with high-risk and relapsed NB. Finding an effective treatment strategy for these patients continues to be a major challenge due to the aggressive phenotypes of these tumors and a myriad of complex mechanisms that promote resistance to treatments and recurrence [3,4,5,6]. The current study focuses on examining the effects of FTY-720 or fingolimod, a drug that is FDA-approved for refractory multiple sclerosis [7,8,9,10,11], in NB. Previous studies have shown that FTY-720 inhibits NB tumor growth by inhibiting sphingosine kinase
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