Bortezomib is cytotoxic to the human growth plate and permanently impairs bone growth in young mice.
Bortezomib is cytotoxic to the human growth plate and permanently impairs bone growth in young mice.
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DOI：
10.1371/journal.pone.0050523
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sävendahl L
中科院分区：
文献类型：
--
作者：
Eriksson E;Zaman F;Chrysis D;Wehtje H;Heino TJ;Sävendahl L
Bortezomib是一种新的蛋白酶体抑制剂，被批准用于治疗成人癌症，最近已被引入儿科临床试验。据我们所知，任何组织特异性的对骨骼发育的副作用还没有被探索过。为了解决这一问题，我们在幼鼠体内和体外培养的大鼠跖骨和人生长板软骨器官培养以及大鼠软骨细胞系中实验研究了Bortezomib的作用。我们发现，Bortezomib在有效阻断泛素/蛋白酶体系统(UPS)的同时，通过增加静息/干状软骨细胞的凋亡，导致小鼠显著的生长障碍。我们的数据支持Bortezomib的局部作用，直接靶向生长板软骨细胞导致骨生长减少，因为没有观察到对血清胰岛素样生长因子-I(IGF-I)水平的抑制。在培养的大鼠跖骨中证实了Bortezomib的局部效应，其中Bortezomib有效地以剂量依赖和不可逆的方式导致生长迟缓，这种作用与增加软骨细胞凋亡有关，主要是静息/干状软骨细胞。在一个独特的培养的人生长板软骨模型中，也评估了Bortezomib的细胞毒性，发现该模型对Bortezomib高度敏感。凋亡途径的机制研究表明，Bortezomib可诱导暴露的软骨细胞中P53和Bax的激活，以及caspase和聚ADP核糖聚合酶(PARP)的裂解。我们在体内和体外证实的观察结果表明，使用Bortezomib治疗的儿童骨骼生长可能受到抑制。因此，我们建议在正在进行的这种有前景的抗癌药物的儿科临床试验中，应该密切监测纵向骨生长。
Bortezomib, a novel proteasome inhibitor approved for the treatment of cancer in adults, has recently been introduced in pediatric clinical trials. Any tissue-specific side effects on bone development have to our knowledge not yet been explored. To address this, we experimentally studied the effects of bortezomib in vivo in young mice and in vitro in organ cultures of rat metatarsal bones and human growth plate cartilage, as well as in a rat chondrocytic cell line. We found that bortezomib while efficiently blocking the ubiquitin/proteasome system (UPS) caused significant growth impairment in mice, by increasing resting/stem-like chondrocyte apoptosis. Our data support a local action of bortezomib, directly targeting growth plate chondrocytes leading to decreased bone growth since no suppression of serum levels of insulin-like growth factor-I (IGF-I) was observed. A local effect of bortezomib was confirmed in cultured rat metatarsal bones where bortezomib efficiently caused growth retardation in a dose dependent and irreversible manner, an effect linked to increased chondrocyte apoptosis, mainly of resting/stem-like chondrocytes. The cytotoxicity of bortezomib was also evaluated in a unique model of cultured human growth plate cartilage, which was found to be highly sensitive to bortezomib. Mechanistic studies of apoptotic pathways indicated that bortezomib induced activation of p53 and Bax, as well as cleavage of caspases and poly-ADP-ribose polymerase (PARP) in exposed chondrocytes. Our observations, confirmed in vivo and in vitro, suggest that bone growth could potentially be suppressed in children treated with bortezomib. We therefore propose that longitudinal bone growth should be closely monitored in ongoing clinical pediatric trials of this promising anti-cancer drug.
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影响因子：
2.4
作者：
Adams, J;Kauffman, M
通讯作者：
Kauffman, M
影响因子：
6.2
作者：
Chagin, AS;Lindberg, MK;Ohlsson, C
通讯作者：
Ohlsson, C
DOI：
10.1073/pnas.95.23.13664
发表时间：
1998-11-10
影响因子：
11.1
作者：
Fearnhead, HO;Rodriguez, J;Lazebnik, YA
通讯作者：
Lazebnik, YA
影响因子：
4
作者：
Chagin, Andrei S.;Karimian, Elham;Savendahl, Lars
通讯作者：
Savendahl, Lars
影响因子：
4.8
作者：
Abad, V;Meyers, JL;Baron, J
通讯作者：
Baron, J