Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth
Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth
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DOI：
10.1593/neo.08466
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Baruchel, Sylvain
中科院分区：
文献类型：
--
作者：
Das, Bikul;Antoon, Roula;Baruchel, Sylvain
角鲨烯是一种类异戊二烯抗氧化剂，是一种潜在的抗化疗毒性的细胞保护剂。我们以前曾发表过，角鲨烯保护轻密度骨髓细胞对抗顺二氨二氯铂（II）（顺铂）诱导的毒性，而不保护体外肿瘤细胞。在这里，我们开发了一种体内小鼠模型顺铂和顺式二氨（环丁烷-1，1-二羧基）铂（II）（卡铂）诱导的毒性，以进一步研究角鲨烯介导的LD-BM细胞保护，包括选择性细胞保护背后的分子机制。我们发现，角鲨烯显着减少顺铂和卡铂治疗小鼠的体重减轻。来自角鲨烯处理小鼠的轻密度骨髓细胞表现出造血集落（集落形成单位-粒细胞巨噬细胞）形成的改善。此外，角鲨烯还保护间充质干细胞集落（集落形成单位-成纤维细胞）免受顺铂和卡铂诱导的毒性。角鲨烯诱导的保护作用与活性氧减少和谷胱甘肽和谷胱甘肽过氧化物酶/谷胱甘肽-S-转移酶水平增加有关。重要的是，角鲨烯不能保护神经母细胞瘤、小细胞癌或髓母细胞瘤异种移植物免受顺铂诱导的毒性。这些结果表明，角鲨烯是一个潜在的候选人，为未来的发展，作为一种细胞保护剂对化疗毒性。
Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum(II) (cisplatin)-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage). Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast) from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathioneperoxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.