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亚硝酰钴胺通过抑制生存信号来增强化疗药物的抗肿瘤作用。

Nitrosylcobalamin potentiates the anti-neoplastic effects of chemotherapeutic agents via suppression of survival signaling.

作者信息

Bauer Joseph A, Lupica Joseph A, Szugye Heidi, Morrison Bei H, Haney Rebecca M, Masci Rhonda K, Lee Rebecca M, Didonato Joseph A, Lindner Daniel J

机构信息

Taussig Cancer Center, Center for Hematology and Oncology Molecular Therapeutics, The Cleveland Clinic Foundation, Cleveland, Ohio, United States of America.

出版信息

PLoS One. 2007 Dec 12;2(12):e1313. doi: 10.1371/journal.pone.0001313.

DOI:10.1371/journal.pone.0001313
PMID:18074035
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2117345/
Abstract

BACKGROUND

Nitrosylcobalamin (NO-Cbl) is a chemotherapeutic pro-drug derived from vitamin B12 that preferentially delivers nitric oxide (NO) to tumor cells, based upon increased receptor expression. NO-Cbl induces Apo2L/TRAIL-mediated apoptosis and inhibits survival signaling in a variety of malignant cell lines. Chemotherapeutic agents often simultaneously induce an apoptotic signal and activation of NF-kappaB, which has the undesired effect of promoting cell survival. The specific aims of this study were to 1) measure the anti-tumor effects of NO-Cbl alone and in combination with conventional chemotherapeutic agents, and to 2) examine the mechanism of action of NO-Cbl as a single agent and in combination therapy.

METHODOLOGY

Using anti-proliferative assays, electrophoretic mobility shift assay (EMSA), immunoblot analysis and kinase assays, we demonstrate an increase in the effectiveness of chemotherapeutic agents in combination with NO-Cbl as a result of suppressed NF-kappaB activation.

RESULTS

Eighteen chemotherapeutic agents were tested in combination with NO-Cbl, in thirteen malignant cell lines, resulting in a synergistic anti-proliferative effect in 78% of the combinations tested. NO-Cbl pre-treatment resulted in decreased NF-kappaB DNA binding activity, inhibition of IkappaB kinase (IKK) enzymatic activity, decreased AKT activation, increased caspase-8 and PARP cleavage, and decreased cellular XIAP protein levels.

CONCLUSION

The use of NO-Cbl to inhibit survival signaling may enhance drug efficacy by preventing concomitant activation of NF-kappaB or AKT.

摘要

背景

亚硝酰钴胺（NO-Cbl）是一种源自维生素B12的化疗前体药物，基于肿瘤细胞受体表达增加，它能优先将一氧化氮（NO）递送至肿瘤细胞。NO-Cbl可诱导Apo2L/TRAIL介导的细胞凋亡，并抑制多种恶性细胞系中的生存信号传导。化疗药物常常同时诱导凋亡信号和NF-κB的激活，而NF-κB的激活会产生促进细胞存活的不良作用。本研究的具体目的是：1）测量NO-Cbl单独使用以及与传统化疗药物联合使用时的抗肿瘤效果；2）研究NO-Cbl作为单一药物及联合治疗时的作用机制。

方法

通过抗增殖试验、电泳迁移率变动分析（EMSA）、免疫印迹分析和激酶试验，我们证明了由于NF-κB激活受到抑制，化疗药物与NO-Cbl联合使用时疗效增强。

结果

在13种恶性细胞系中，对18种化疗药物与NO-Cbl的联合使用进行了测试，结果显示78%的测试组合产生了协同抗增殖效应。NO-Cbl预处理导致NF-κB DNA结合活性降低、IκB激酶（IKK）酶活性受到抑制、AKT激活减少、caspase-8和PARP裂解增加以及细胞XIAP蛋白水平降低。

结论

使用NO-Cbl抑制生存信号传导可能通过防止NF-κB或AKT的同时激活来提高药物疗效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/ee6357f357f8/pone.0001313.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/bf44d843b378/pone.0001313.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/355d31b6f9c6/pone.0001313.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/1fc7d4238a31/pone.0001313.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/b412aef2746d/pone.0001313.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/8c83044af0fa/pone.0001313.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/80c4161e0e63/pone.0001313.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/ee6357f357f8/pone.0001313.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/bf44d843b378/pone.0001313.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/355d31b6f9c6/pone.0001313.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/1fc7d4238a31/pone.0001313.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/b412aef2746d/pone.0001313.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/8c83044af0fa/pone.0001313.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/80c4161e0e63/pone.0001313.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/246a/2117345/ee6357f357f8/pone.0001313.g007.jpg

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