Inhibition of Paclitaxel-induced Decreases in Calcium Signaling
Inhibition of Paclitaxel-induced Decreases in Calcium Signaling
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DOI：
10.1074/jbc.m112.385070
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发表时间：
2012-11-02
影响因子：
4.8
通讯作者：
Ehrlich, Barbara E.
中科院分区：
文献类型：
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作者：
Benbow, Jennifer H.;Mann, Taylor;Ehrlich, Barbara E.
周围神经病变是多种化疗药物（包括紫杉醇 (Taxol (R)) 和长春新碱）治疗引起的最严重且不可逆的副作用之一。需要制定策略来抑制这种不良副作用而不改变这些药物的化疗作用。我们之前在导致紫杉醇诱导的周围神经病变的细胞途径中发现了两种蛋白质：神经元钙传感器-1 (NCS-1) 和钙蛋白酶。长期使用紫杉醇治疗会诱导钙蛋白酶激活、NCS-1 降解和细胞内钙信号传导丧失。本文通过测试在现有化疗药物方案中添加两种候选化合物（锂和异丁司特）的效果，重点了解预防周围神经病变的分子基础。我们发现，对用紫杉醇或长春新碱治疗的神经母细胞瘤细胞同时给予锂或异丁司特可抑制钙蛋白酶的激活以及与这些化疗药物相关的 NCS-1 水平和钙信号传导的降低。添加任一候选化合物后，紫杉醇改变微管形成的能力没有改变。这些结果使我们表明，在保持治疗效果的同时，可以预防化疗药物造成的不必要的和不可逆的损害。具体来说，在现有化疗方案中添加锂或异丁司特有可能预防化疗引起的周围神经病变。
Peripheral neuropathy is one of the most severe and irreversible side effects caused by treatment from several chemotherapeutic drugs, including paclitaxel (Taxol (R)) and vincristine. Strategies are needed that inhibit this unwanted side effect without altering the chemotherapeutic action of these drugs. We previously identified two proteins in the cellular pathway that lead to Taxol-induced peripheral neuropathy, neuronal calcium sensor-1 (NCS-1) and calpain. Prolonged treatment with Taxol induces activation of calpain, degradation of NCS-1, and loss of intracellular calcium signaling. This paper has focused on understanding the molecular basis for prevention of peripheral neuropathy by testing the effects of addition of two candidate compounds to the existing chemotherapeutic drug regime: lithium and ibudilast. We found that the co-administration of either lithium or ibudilast to neuroblastoma cells that were treated with Taxol or vincristine inhibited activation of calpain and the reductions in NCS-1 levels and calcium signaling associated with these chemotherapeutic drugs. The ability of Taxol to alter microtubule formation was unchanged by the addition of either candidate compound. These results allow us to suggest that it is possible to prevent the unnecessary and irreversible damage caused by chemotherapeutic drugs while still maintaining therapeutic efficacy. Specifically, the addition of either lithium or ibudilast to existing chemotherapy treatment protocols has the potential to prevent chemotherapy-induced peripheral neuropathy.