叔丁基对苯二酚上调Nrf2调控的基因表达并减轻环磷酰胺导致的小鼠血液毒性

doi:10.5246/jcps.2014.01.006

中国药学(英文版)

叔丁基对苯二酚上调Nrf2调控的基因表达并减轻环磷酰胺导致的小鼠血液毒性

阙琳玲, 王欣竹, 钱鹏展, 曹宝山, 王夔, 余四旺^*

1. 北京大学医学部药学院化学生物学系, 北京 100191
2. 北京大学附属第三医院肿瘤中心肿瘤化疗科, 北京 100191

收稿日期:2013-06-17 修回日期:2013-07-10 出版日期:2014-01-23 发布日期:2014-01-22
通讯作者: 余四旺*
作者简介:*Corresponding author. Tel.: +86-10-82801539; E-mail: swang_yu@bjmu.edu.cn
基金资助:
National Natural Science Foundation (Grant No. 81272468 and 21001011) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education.

Upregulation of Nrf2-regulated gene expression by tBHQ alleviates cyclophosphamide-induced hematotoxicity in mice

Linling Que, Xinzhu Wang, Pengzhan Qian, Baoshan Cao, Kui Wang, Siwang Yu^*

1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Oncology, Cancer Center, Peking University Third Hospital, Beijing 100191, China

Received:2013-06-17 Revised:2013-07-10 Online:2014-01-23 Published:2014-01-22
Contact: Siwang Yu*
About author:*Corresponding author. Tel.: +86-10-82801539; E-mail: swang_yu@bjmu.edu.cn
Supported by:
National Natural Science Foundation (Grant No. 81272468 and 21001011) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education.

摘要/Abstract

摘要：

血液毒性 (或称骨髓抑制)是癌症化疗最常见的剂量限制毒副作用, 而转录因子Nrf2控制着包括骨髓在内的许多组织对化学刺激的敏感性。本文研究了叔丁基对苯二酚(tBHQ)对小鼠外周血细胞中Nrf2调控的基因表达和环磷酰胺 (CTX)导致的血液毒性的影响。CTX处理导致了小鼠外周血有核细胞的凋亡和白细胞减少, 伴随着骨髓造血细胞的动员。tBHQ处理则可以在体外和体内激活RAW264.7小鼠巨噬细胞和外周血细胞中Nrf2信号和下游基因如血红素氧化酶1和谷胺酸半胱氨酸连接酶催化亚基等的表达; 同时, tBHQ预处理可以减轻CTX导致的小鼠外周血有核细胞的凋亡和白细胞减少, 说明Nrf2可能在减轻CTX血液毒性中发挥作用。本文的研究有助于加深对化疗所致血液毒性的了解, 并提示Nrf2可能作为减轻化疗毒副作用的化疗保护剂的药物靶标。

关键词: 环磷酰胺, 血液毒性, 外周血细胞, 骨髓, 叔丁基对苯二酚, 转录因子Nrf2

Abstract:

Hematological toxicity (bone marrow suppression) is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal coordinator of cellular defensive responses against chemical insults in many tissues including bone marrow. In the present study, the effects of tert-butylhydroquinone (tBHQ) on the expression of Nrf2-regulated genes in peripheral blood cells and cyclophosphamide (CTX)-induced hematotoxicity in mice were investigated. CTX induced apoptosis of peripheral blood nucleated cells and leukopenia in mice, accompanied by mobilization of bone marrow hematopoietic cells. tBHQ treatment induced the expression of Nrf2-regulated genes such as heme oxygenase 1 (HO1) and glutamate-cysteine ligase catalytic subunit (GCLC) in RAW264.7 mouse macrophage cells and peripheral blood cells both in vitro and in vivo. Interestingly, pretreatment with tBHQ alleviated CTX-induced mouse peripheral blood cell apoptosis and leukopenia in vivo, indicating possible involvement of Nrf2 in the protection against CTX-induced hematotoxicity. This study provides new information on the chemotherapy-induced hematotoxicity, and suggests Nrf2 could serve as a target for the development of chemoprotectants against hematotoxicity.

Key words: Cyclophosphamide, Hematotoxicity, Peripheral blood cells, Bone marrow, tBHQ, Nrf2

中图分类号:

R915

Supporting: National Natural Science Foundation (Grant No. 81272468 and 21001011) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education.

阙琳玲, 王欣竹, 钱鹏展, 曹宝山, 王夔, 余四旺*. 叔丁基对苯二酚上调Nrf2调控的基因表达并减轻环磷酰胺导致的小鼠血液毒性[J]. 中国药学(英文版), DOI: 10.5246/jcps.2014.01.006.

Linling Que, Xinzhu Wang, Pengzhan Qian, Baoshan Cao, Kui Wang, Siwang Yu* . Upregulation of Nrf2-regulated gene expression by tBHQ alleviates cyclophosphamide-induced hematotoxicity in mice[J]. Journal of Chinese Pharmaceutical Sciences, DOI: 10.5246/jcps.2014.01.006.

参考文献

[1] Lyman, G.H.; Kuderer, N.M.; Crawford, J.; Wolff, D.A.; Culakova, E.; Poniewierski, M.S.; Dale, D.C. Cancer. 2011, 117, 1917–1927.

[2] Friberg, L.E.; Karlsson, M.O. Invest New Drugs. 2003, 21, 183–194.

[3] Cancelas, J.A.; Koevoet, W.L.; de Koning, A.E.; Mayen, A.E.; Rombouts, E.J.; Ploemacher, R.E. Blood. 2000, 96, 498–505.

[4] Sangeetha, P.; Das, U.N.; Koratkar, R.; Suryaprabha, P. Free Radic Biol. Med. 1990, 8, 15–19.

[5] Ladner, C.; Ehninger, G.; Gey, K.F.; Clemens, M.R. Cancer Chemother. Pharmacol. 1989, 25, 210–212.

[6] Alenzi, F.Q.; El-Bolkiny Yel, S.; Salem, M.L. Br. J. Biomed. Sci. 2010, 67, 20–28.

[7] Abd-Allah, A.R.; Al-Majed, A.A.; Al-Yahya, A.A.; Fouda, S.I.; Al-Shabana, O.A. Arch. Toxicol. 2005, 79, 406–413.

[8] Husain, K.; Whitworth, C.; Rybak, L.P. Pharmacol. Res. 2004, 50, 291–300.

[9] Neuwelt, E.A.; Pagel, M.A.; Kraemer, D.F.; Peterson, D.R.; Muldoon, L.L. J. Pharmacol. Exp. Ther. 2004, 309, 594–599.

[10] Budd, G.T.; Ganapathi, R.; Bukowski, R.M.; Murthy, S. Eur. J. Cancer. 1996, 32A Suppl 4, S43–45.

[11] Pratibha, R.; Sameer, R.; Rataboli, P.V.; Bhiwgade, D.A.; Dhume, C.Y. Eur. J. Pharmacol. 2006, 532, 290–293.

[12] Muldoon, L.L.; Walker-Rosenfeld, S.L.; Hale, C.; Purcell, S.E.; Bennett, L.C.; Neuwelt, E.A. J. Pharmacol. Exp. Ther. 2001, 296, 797–805.

[13] Numazawa, S.; Sugihara, K.; Miyake, S.; Tomiyama, H.; Hida, A.; Hatsuno, M.; Yamamoto, M.; Yoshida, T. Basic Clin. Pharmacol. Toxicol. 2011, 108, 40–45.

[14] Itoh, K.; Mimura, J.; Yamamoto, M. Antioxid. Redox. Signal. 2010, 13, 1665–1678.

[15] Zhu, H.; Zhang, L.; Itoh, K.; Yamamoto, M.; Ross, D.; Trush, M.A.; Zweier, J.L.; Li, Y. Free Radic. Biol. Med. 2006, 41, 132–143.

[16] Cao, B.S.; Que, L.L.; Zhang, Y.; Che, S.; Yin, W.Z.; Wang, S.F; Ma, L.W.; Yu, S.W. Tumor. 2012, 32, 124–129.

[17] Jurado, J.M.; Sanchez, A.; Pajares, B.; Perez, E.; Alonso, L.; Alba, E. Clin. Transl. Oncol. 2008, 10, 583–586.

[18] Osell, R.; Moreno, I.; Maestre, J.; Olazabal, A.; Carles, J.; Barnadas, A.; Abad-Esteve, A.; Ribelles, N.; Canela, M. J. Surg. Oncol. 1990, 45, 124–130.

[19] Zhao, X.X; Yan, D.H.; Wang, H.P.; Tian, K.Y.; Du, C.X. Lab. Anim. Comparat. Med. 1998, 18, 12–14.

[20] Salem, M.L.; El-Naggar, S.A.; Cole, D.J. Cell Immunol. 2010, 261, 134–143.

叔丁基对苯二酚上调Nrf2调控的基因表达并减轻环磷酰胺导致的小鼠血液毒性

Upregulation of Nrf2-regulated gene expression by tBHQ alleviates cyclophosphamide-induced hematotoxicity in mice

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 9

编辑推荐

Metrics

本文评价

[1]	张林, 丁洁卫, 王阳, 金晓宣, 葛伟东, 黄淑婷, 李玉婷. 埃罗妥珠单抗治疗难治性/复发性多发性骨髓瘤临床试验效果的Meta分析[J]. 中国药学(英文版), 2017, 26(7): 528-533.
[2]	张林, 金晓宣, 黄淑婷, 徐雯宇, 丁洁卫. 卡非佐米及其组合药物在治疗多发性骨髓瘤的有效性及安全性分析[J]. 中国药学(英文版), 2017, 26(3): 222-229.
[3]	鲁兖, 刘丽娜, 楼洪刚, 徐翔^*. 参附注射液对化疗引起的骨髓抑制的保护作用[J]. , 2012, 21(4): 345-349.
[4]	李晓娜, 于宁, 张建美, 林文斯, 凌笑梅^*, 富戈, 李润涛, 崔景荣. 在线SPE HPLC-DAD方法测定大鼠血浆环磷酰胺浓度[J]. , 2012, 21(2): 156-161.
[5]	郑愉, 孟祥豹, 李树春, 黄河清, 李中军^, 李庆^. 5-半乳糖基修饰环磷酰胺衍生物的合成及其抗肿瘤活性研究 [J]. , 2010, 19(5): 327-340.
[6]	杨青, 朱继让, 孙崎^, 崔景荣, 李润涛, 葛泽梅^. 新型环磷酰胺前药: 环磷酰胺哌嗪季铵盐的构效关系[J]. , 2010, 19(1): 24-33.
[7]	刘墨, 葛泽梅^, 程铁明, 李润涛^. 一类环磷酰胺双哌嗪季铵盐类抗肿瘤化合物的合成[J]. , 2009, 18(4): 320-325.
[8]	王珮珮, 张玉, 王凯平^*, 李珂. 当归多糖铁治疗溶血性贫血及骨髓损伤小鼠的实验研究 [J]. , 2008, 17(3): 197-202.
[9]	王洪斌, 郑钦岳, 孙盛川, 刘宝云, 沈有安, 唐惠兰, 鞠佃文, 方军. 商陆多糖I对给环磷酰胺及⁶⁰Co照射小鼠造血功能的保护作用[J]. , 1995, 4(2): 89-98.