FTY-720 induces apoptosis in neuroblastoma via multiple signaling pathways
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Ingo Lange1, Italo Espinoza-Fuenzalida1, Mourad Wagdy Ali1, Laura Espana Serrano1 and Dana-Lynn T. Koomoa1
1University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Hilo, HI 96720, USA
Dana-Lynn T. Koomoa, email: [email protected]
Ingo Lange, email: [email protected]
Keywords: neuroblastoma; calcium; FTY720; TRPM7; channel
Received: June 08, 2017 Accepted: October 17, 2017 Published: November 06, 2017
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.
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