National Institute of Health and Medical Research, Nantes, France.
Cancer. 2012 Feb 1;118(3):750-60. doi: 10.1002/cncr.26336. Epub 2011 Jul 12.
Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis.
The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines.
Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used.
The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma.
骨肉瘤是最常见的原发性恶性骨肿瘤，主要发生在年轻人中，发病高峰在 18 岁。阿朴吗啡和洛伐他汀在多种癌细胞系中均具有抗肿瘤活性。阿朴吗啡是一种 1,1-双膦酸酯酯，可增加 3-羟基-3-甲基戊二酰基辅酶 A（HMG-CoA）还原酶的降解率，HMG-CoA 还原酶是甲羟戊酸途径中的限速酶，而洛伐他汀竞争性抑制 HMG-CoA 还原酶的酶活性，从而阻止蛋白质异戊烯化和胆固醇合成。
本报告的作者研究了阿朴吗啡和洛伐他汀联合治疗对体外人源和鼠源骨肉瘤细胞系以及体内鼠源骨肉瘤同源模型的影响。阿朴吗啡和洛伐他汀协同降低了两种鼠源和人源骨肉瘤细胞系的活力并诱导其凋亡。
与单独使用洛伐他汀相比，联合使用阿朴吗啡和洛伐他汀可显著降低 HMG-CoA 还原酶的酶水平。因此，在阿朴吗啡存在的情况下，洛伐他汀诱导的未异戊烯化 ras 相关蛋白 1A 的积累增加。在添加甲羟戊酸或香叶基香叶基焦磷酸，即靶酶 HMG-CoA 还原酶下游的两条甲羟戊酸途径中间产物后，对细胞活力、凋亡和蛋白质异戊烯化的所有协同作用都被克服。这证实了骨肉瘤细胞中协同作用的机制是通过增强 HMG-CoA 还原酶的抑制作用。最后，与单独治疗相比，阿朴吗啡和洛伐他汀联合治疗携带 POS-1 骨肉瘤的小鼠可显著减少肿瘤进展，而在使用的剂量下，单独治疗没有效果。
本研究结果表明，阿朴吗啡和洛伐他汀联合治疗可能是骨肉瘤的一种新的治疗策略。
