The short chain cell-permeable ceramide (C6) restores cell apoptosis and perifosine sensitivity in cultured glioblastoma cells.
Primary glioblastoma multiforme is the most malignant form of astrocytic tumor with an average survival of approximately 12-14 months. The combination of novel Akt inhibitors with anti-cancer therapeutics has achieved improved anti-tumor efficiency. In the current study, we examined the synergistic anti-cancer ability of Akt inhibitor perifosine in combination with short-chain ceramide (C6) against glioblastoma cells (U87MG and U251MG), and studied the underlying mechanisms. We found that perifosine, which blocked Akt/mammalian target of rapamycin activation, only induced moderate cell death and few cell apoptosis in cultured glioblastoma cells. On the other hand, perifosine administration induced significant protective autophagy, which inhibited cell apoptosis induction. Inhibition of autophagy by 3-methyaldenine or by autophagy-related gene-5 RNA interference significantly enhanced perifosine-induced apoptosis and cytotoxicity. We found that the short chain cell-permeable ceramide (C6) significantly enhanced cytotoxic effects of perifosine in cultured glioblastoma cells. For mechanism study, we observed that ceramide (C6) inhibited autophagy induction to restore cell apoptosis and perifosine sensitivity. In conclusion, our study suggests that autophagy inhibition by ceramide (C6) restores perifosine-induced apoptosis and cytotoxicity in glioblastoma cells.
Department of Neurosurgery, The First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, 215000, Jiangsu, People's Republic of China.
Li-sen
LS
Qin
Zheng-quan
ZQ
Yu
Shi-ming
SM
Zhang
Guan
G
Sun
Jian
J
Zhu
Jin
J
Xu
Jun
J
Guo
Lin-shan
LS
Fu
D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology*; D005909:Glioblastoma / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002518:Ceramides; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases