Chemotherapeutic sensitization by endoplasmic reticulum stress: increasing the efficacy of taxane against prostate cancer.
Chemotherapeutic sensitization by endoplasmic reticulum stress: increasing the efficacy of taxane against prostate cancer.
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DOI：
10.4161/cbt.8.2.7087
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发表时间：
2009-01
影响因子：
3.6
通讯作者：
Ip C
中科院分区：
文献类型：
--
作者：
Wu Y;Fabritius M;Ip C
紫杉烷类药物是治疗抗雄激素治疗失败后前列腺癌复发的一线药物。需要使紫杉烷类药物更加有效，因为它们仅提供姑息性益处。利用内质网（ER）应激死亡信号来增强药物疗效尚未被描述。人类 PC-3 细胞被用作激素难治性前列腺癌的模型。毒胡萝卜素和甲基硒酸（MSA）被检查为敏化剂。 Thapsigargin 是一种经典的 ER 应激诱导剂。我们的小组最近研究了 MSA 在诱导 ER 应激中的活性。通过使用细胞死亡 ELISA 试剂盒测量细胞凋亡来评估单一药物和各种组合的功效。 Thapsigargin 使紫杉醇或多西紫杉醇的细胞杀伤效力增加了 10 至 12 倍，而 MSA 则增加了 5 至 8 倍。由于毒胡萝卜素因其毒性而未用于临床，因此后续实验均采用MSA进行。为了检验 ER 应激阈值水平对于化疗致敏至关重要的假设，研究了旨在抑制 MSA 引起的 ER 应激严重程度的三种不同方法。降低内质网应激会持续减弱 MSA/紫杉烷的功效。 GADD153 是一种促凋亡转录因子，在内质网应激期间上调。通过 siRNA 敲低 GADD153 也降低了 MSA/紫杉烷的细胞杀伤作用。内在和外在的细胞凋亡途径均参与致敏机制。我们的研究支持这样的观点：整合内质网应激细胞凋亡反应有利于化疗敏化。
Taxanes are first line drugs for treating prostate cancer recurrence after the failure of anti-androgen therapy. There is a need to make taxanes more effective since they only provide palliative benefit. Exploiting endoplasmic reticulum (ER) stress death signaling to enhance drug efficacy has not been delineated. Human PC-3 cells were used as a model of hormone refractory prostate cancer. Thapsigargin and methylseleninic acid (MSA) were examined as sensitizers. Thapsigargin is a classic ER stress inducer. The activity of MSA in inducing ER stress has recently been studied by our group. The efficacy of single drug and the various combinations was evaluated by measuring apoptosis with a cell death ELISA kit. Thapsigargin increased the cell killing potency of paclitaxel or docetaxel by 10- to 12-fold, while MSA caused a 5- to 8-fold increase. Since thapsigargin is not used clinically because of its toxicity, the follow-up experiments were done with MSA. To test the hypothesis that a threshold level of ER stress is crucial to chemotherapeutic sensitization, three different approaches designed to dampen the severity of ER stress induced by MSA were examined. Lowering ER stress consistently attenuated the efficacy of MSA/taxane. GADD153 is a pro-apoptotic transcription factor which is up-regulated during ER stress. Knocking down GADD153 by siRNA also reduced the cell killing effect of MSA/taxane. Both the intrinsic and extrinsic apoptotic pathways were involved in the sensitization mechanism. Our study supports the idea that marshalling ER stress apoptotic response is conducive to chemotherapeutic sensitization.
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