Analysis of molecular mechanism of cytotoxicity with cytoplasmic vacuolation by drugs

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860487
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Legal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: FUNAKOSHI TAKESHI 東京医科歯科大学, 医歯(薬)学総合研究科, 助教 (40444715)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 塩基性薬物 / コレステロール / ネクロトーシス / 細胞内空胞化

Outline of Final Research Achievements

We have shown previously that norephedrine (Nor), a basic drug, induces cell toxicity that are associated with massive cytoplasmic vacuolation in SH-SY5Y human neuroblastoma cells. To reveal the molecular mechanism underling cytotoxicity with vacuolation by basic drugs, we examined alteration of gene expression profile during Nor exposure in the cells. DNA microarray and realtime PCR analysis revealed that the genes for cholesterol biosynthesis were increased after exposure to Nor. Concomitant with the observation, the master transcriptional regulator of cholesterol homeostasis, SREBP-2, was activated by Nor.In addition, we found that the cell death by Nor could be suppressed by Nec-1s, an inhibitor of necroptosis. Furthermore, abrogation of SREBP-2 activation by inhibitor botulin efficiently reduced the cell death by Nor.
Taken together, our results indicate that the excessive accumulation of cholesterol should underlie the neuronal cell death by basic drug exposure.

Free Research Field

医歯薬学