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Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo
Author(s) -
Segerström Lova,
Baryawno Ninib,
Sveinbjörnsson Baldur,
Wickström Malin,
Elfman Lotta,
Kogner Per,
Johnsen John Inge
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26268
Subject(s) - neuroblastoma , pi3k/akt/mtor pathway , protein kinase b , cancer research , p70 s6 kinase 1 , gsk 3 , apoptosis , cyclin d1 , biology , kinase , in vivo , cell cycle , signal transduction , microbiology and biotechnology , cell culture , biochemistry , genetics
Activation of the PI3K/Akt signaling pathway is correlated with poor prognosis in neuroblastoma, the most common and deadly extracranial tumor of childhood. In this study, we show that the small‐molecule inhibitors of phosphoinositide‐dependent protein kinase‐1 (PDK1) OSU03012 and the dual class I PI3K/mTOR inhibitor PI103 have profound effects on neuroblastoma survival in vitro and in vivo . Both OSU03012 and PI103 inhibited neuroblastoma growth in vitro . In treated cells, OSU03012 induced apoptosis and an S phase cell cycle arrest, whereas only minor apoptosis was detected in PI103 treated cells together with a G1 arrest. Both OSU03012 and PI103 downregulated phosphorylation of Akt and inhibited the downstream targets glycogen synthase kinase‐3β (GSK3β) and p70 S6 kinase‐1 (S6K1), as well as downregulated the expression of cyclin D1 and Mycn protein. Neuroblastoma cells expressing high levels of Mycn were more sensitive to OSU03012 or PI103 compared with cells expressing low Mycn levels. Both compounds significantly inhibited the growth of established, subcutaneous MYCN ‐amplified neuroblastoma xenografts in nude NMRI nu/nu mice. These results suggest that inhibition of the PI3K/Akt signaling pathway represent a clinical relevant target for the treatment of patients with high‐risk MYCN ‐amplified neuroblastoma.