FTY-720 induces apoptosis in neuroblastoma via multiple signaling pathways

// Ingo Lange 1 , Italo Espinoza-Fuenzalida 1 , Mourad Wagdy Ali 1 , Laura Espana Serrano 1 and Dana-Lynn T. Koomoa 1 1 University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Hilo, HI 96720, USA Correspondence to: Dana-Lynn T. Koomoa, email: danalynn@hawaii.edu Ingo Lange, email: ingo@hawaii.edu Keywords: neuroblastoma; calcium; FTY720; TRPM7; channel Received: June 08, 2017      Accepted: October 17, 2017      Published: November 06, 2017 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.