Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro.
Medulloblastoma is a malignant paediatric central nervous system tumor with a poor prognosis, stimulating the evaluation of improved treatment strategies. Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, is currently used to treat patients with hypercholesterolemia. This compound also inhibits the production of non-steroidal mevalonate derivatives that are implicated in the control of cellular proliferation, and can induce cell-cycle arrest in vitro. We recently showed that lovastatin inhibited growth and promoted apoptosis of neuroblastoma, the peripheral nervous system 'cousin' of medulloblastoma. Therefore the potential of lovastatin as a possible anticancer drug against medulloblastoma was evaluated in vitro. Four medulloblastoma cell lines, Daoy, UW228, D341 Med and D283 Med, were treated with 1-40 microM of lovastatin in vitro. Analysis of cell morphologic changes, cell viability, DNA fragmentation and flow cytometry in all four cell lines showed growth inhibition and induction of apoptosis with lovastatin treatment. As little as 10 microM of lovastatin was sufficient to cause a marked reduction in cell numbers, and more than 20 microM of lovastatin induced >90% cells to undergo apoptosis, after intervals ranging between 36 and 96 h, depending on the cell line. Lovastatin induced apoptosis in these cell lines was concomitant with cell cycle arrest in G1. The attached cell lines UW228 and Daoy were more sensitive to lovastatin than D283 Med and D341 Med. Daoy cells which survived several cycles of lovastatin treatment could still be induced to undergo apoptosis after longer treatment times. The efficient induction of apoptosis by lovastatin favours this drug as a potential new avenue of therapeutic intervention for medulloablastoma.
Macaulay
R J
RJ
Department of Pathology, University of Saskatchewan, Saskatoon, Canada. macaulay@duke.usask.ca
Wang
W
W
Dimitroulakos
J
J
Becker
L E
LE
Yeger
H
H
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000473:pathology*; D002648:Child; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity; D008148:Lovastatin / Q000633:toxicity*; D008527:Medulloblastoma / Q000473:pathology*; D014407:Tumor Cells, Cultured
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin