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 strateg ies. Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coen zyme A reductase, is currently used to treat patients with hypercholesterol emia. This compound also inhibits the production of non-steroidal mevalonat e derivatives that are implicated in the control of cellular proliferation, and can induce cell-cycle arrest in vitro. We recently showed that lovasta tin inhibited growth and promoted apoptosis of neuroblastoma, the periphera l nervous system 'cousin' of medulloblastoma. Therefore the potential of lo vastatin as a possible anticancer drug against medulloblastoma was evaluate d in vitro. Four medulloblastoma cell lines, Daoy, UW228, D341 Med and D283 Med, were treated with 1-40 mu M Of lovastatin in vitro. Analysis of cell morphologic changes, cell viability, DNA fragmentation and flow cytometry i n all four cell lines showed growth inhibition and induction of apoptosis w ith lovastatin treatment. As little as 10 mu M of lovastatin was sufficient to cause a marked reduction in cell numbers, and more than 20 mu M of lova statin induced >90% cells to undergo apoptosis, after intervals ranging bet ween 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 attac hed cell lines UW228 and Daoy were more sensitive to lovastatin than D283 M ed and D341 Med. Daoy cells which survived several cycles of lovastatin tre atment could still be induced to undergo apoptosis after longer treatment t imes. The efficient induction of apoptosis by lovastatin favours this drug as a potential new avenue of therapeutic intervention fur medulloablastoma.