Mevastatin induces degeneration and decreases viability of cAMP-induced differentiated neuroblastoma cells in culture by inhibiting proteasome activity, and mevalonic acid lactone prevents these effects.
Statins with a closed-ring structure (mevastatin, lovastatin, and simvastatin) and with an open-ring structure (pravastatin and fluvastatin) are widely used in the human population to manage hypercholesterolemia. These statins may have neuroprotective or neurotoxic effects, but these effects remain controversial. We have utilized adenosine 3',5'-cyclic monophosphate-induced terminally differentiated murine neuroblastoma (NB) cells in culture as an experimental model to study the effect of statins. Results showed that mevastatin induced degenerative changes and reduced the viability of differentiated NB cells by inhibiting proteasome activity. Lactacystin, an established inhibitor of proteasome, also produced similar degenerative changes in these cells. In contrast, pravastatin neither affected the degeneration and viability of differentiated NB cells nor the proteasome activity. High-performance liquid chromatography (HPLC) analysis of the extract obtained from mevastatin-treated growth medium and differentiated cells revealed that about 50% of mevastatin is converted to an open-ring structure in the growth medium; however, differentiated cells did not convert any portion of mevastatin into an open-ring structure and accumulated only mevastatin with a closed-ring structure. Mevalonic acid lactone by itself did not affect the viability of differentiated NB cells or the proteasome activity, but it completely prevented mevastatin-induced degeneration and decreased viability by reducing the uptake of mevastatin and by blocking its action on proteasome activity. Mevalonic acid failed to prevent lactacystin-induced degeneration and inhibition of proteasome activity. Our results suggest that mevastatin could act as a neurotoxic agent or neuroprotective agent, depending upon the extent of its hydrolysis to an open-ring structure and the level of mevalonic acid.
Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Bipin
B
Kumar
Cynthia
C
Andreatta
William T
WT
Koustas
William C
WC
Cole
Judith
J
Edwards-Prasad
Kedar N
KN
Prasad
D000818:Animals; D000924:Anticholesteremic Agents / Q000032:analysis / Q000494:pharmacology*; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry; D000242:Cyclic AMP / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000924:Anticholesteremic Agents; D003470:Culture Media; D009097:Multienzyme Complexes; C012258:mevastatin; C015367:mevalonolactone; D008148:Lovastatin; D000242:Cyclic AMP; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D017035:Pravastatin; D008798:Mevalonic Acid