The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation
The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation
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DOI：
10.1002/ijc.24758
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发表时间：
2010-01-01
影响因子：
6.4
通讯作者：
Gramatzki, Martin
中科院分区：
文献类型：
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作者：
Guenther, Andreas;Gordon, Sharon;Gramatzki, Martin
含氮二膦酸盐(N-BPS)是治疗多发性骨髓瘤的有效抗骨溶解药物。临床前研究也表明，这些药物在体外具有直接的抗肿瘤作用，并可以在各种动物模型中减轻肿瘤负担，尽管目前尚不清楚这种作用是由直接作用于肿瘤细胞还是通过抑制骨吸收引起的。N-BPS通过抑制破骨细胞中的法尼基焦磷酸合成酶来防止骨髓瘤的骨破坏，从而阻止小GTPase信号蛋白的预烯化。在这项研究中，利用没有并发骨骼病变的浆细胞瘤异种移植模型，唑来膦酸(ZOL)治疗显著延长了接种人INA-6浆细胞的严重联合免疫缺陷小鼠的生存时间。在临床相关剂量的ZOL治疗后，对来自腹膜腔的INA-6肿瘤的组织学分析显示，与聚(ADP-核糖)聚合酶裂解相关的广泛的凋亡区。此外，对肿瘤匀浆的Western印迹分析表明，未戊烯基化的Rap1a积累，表明非骨骼肿瘤摄取ZOL，并抑制法尼基焦磷酸合成酶。这些研究首次提供了明确的证据，证明N-BPS在体内浆细胞肿瘤中具有直接的抗肿瘤作用，其执行的分子机制与在破骨细胞中观察到的类似。
Nitrogen-containing bisphosphonates (N-BPs) are effective antiosteolytic agents in patients with multiple myeloma. Preclinical studies have also demonstrated that these agents have direct antitumor effects in vitro and can reduce tumor burden in a variety of animal models, although it is not clear whether such effects are caused by direct actions on tumor cells or by inhibition of bone resorption. N-BPs prevent bone destruction in myeloma by inhibiting the enzyme farnesyl pyrophosphate synthase in osteoclasts, thereby preventing the prenylation of small GTPase signaling proteins. In this study, utilizing a plasmacytoma xenograft model without complicating skeletal lesions, treatment with zoledronic acid (ZOL) led to significant prolongation of survival in severe combined immunodeficiency mice inoculated with human INA-6 plasma cells. Following treatment with a clinically relevant dose of ZOL, histological analysis of INA-6 tumors from the peritoneal cavity revealed extensive areas of apoptosis associated with poly (ADP-ribose) polymerase cleavage. Furthermore, Western blot analysis of tumor homogenates demonstrated the accumulation of unprenylated Rap1A, indicative of the uptake of ZOL by nonskeletal tumors and inhibition of farnesyl pyrophosphate synthase. These studies provide, for the first time, clear evidence that N-BPs have direct antitumor effects in plasma cell tumors in vivo and this is executed by a molecular mechanism similar to that observed in osteoclasts.