Macaulay R J, Wang W, Dimitroulakos J, Becker L E, Yeger H
Department of Pathology, University of Saskatchewan, Saskatoon, Canada.
J Neurooncol. 1999 Mar;42(1):1-11. doi: 10.1023/a:1006164406202.
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.
髓母细胞瘤是一种预后较差的儿童恶性中枢神经系统肿瘤，这促使人们对改进治疗策略进行评估。洛伐他汀是3-羟基-3-甲基戊二酰辅酶A还原酶的竞争性抑制剂，目前用于治疗高胆固醇血症患者。这种化合物还能抑制与细胞增殖控制有关的非甾体甲羟戊酸衍生物的产生，并能在体外诱导细胞周期停滞。我们最近发现，洛伐他汀可抑制神经母细胞瘤（髓母细胞瘤的外周神经系统“近亲”）的生长并促进其凋亡。因此，我们在体外评估了洛伐他汀作为一种可能的抗髓母细胞瘤抗癌药物的潜力。用1-40微摩尔的洛伐他汀体外处理四种髓母细胞瘤细胞系，即Daoy、UW228、D341 Med和D283 Med。对所有四种细胞系的细胞形态变化、细胞活力、DNA片段化和流式细胞术分析表明，洛伐他汀处理可抑制细胞生长并诱导凋亡。低至10微摩尔的洛伐他汀就足以使细胞数量显著减少，超过20微摩尔的洛伐他汀在36至96小时的不同时间间隔后，可诱导超过90%的细胞发生凋亡，具体时间取决于细胞系。洛伐他汀在这些细胞系中诱导凋亡的同时伴有细胞周期在G1期停滞。贴壁细胞系UW228和Daoy比D283 Med和D341 Med对洛伐他汀更敏感。在经过几个周期洛伐他汀处理后存活下来的Daoy细胞，在更长时间的处理后仍可被诱导发生凋亡。洛伐他汀有效诱导凋亡，使其成为髓母细胞瘤治疗干预的潜在新途径。
