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铋卟啉通过意外的非金属硫蛋白依赖机制拮抗顺铂诱导的肾毒性。

Bismuth Porphyrin Antagonizes Cisplatin-Induced Nephrotoxicity via Unexpected Metallothionein-Independent Mechanisms.

作者信息

Wang Runming, Wang Suyu, Chan Shing, Wang Yuchuan, Zhang Yufeng, Zuo Zhong, Chi-Fung Chan Godfrey, Li Hongyan, Sun Hongzhe

机构信息

Department of Chemistry, The University of Hong Kong, Pokfulam Road, Pok Fu Lam, Hong Kong S.A.R., P.R. China.

Department of Paediatrics & Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam Road, Pok Fu Lam, Hong Kong S.A.R., P.R. China.

出版信息

iScience. 2020 May 22;23(5):101054. doi: 10.1016/j.isci.2020.101054. Epub 2020 Apr 12.

DOI:10.1016/j.isci.2020.101054
PMID:32353763
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7191608/
Abstract

Cisplatin (CDDP) has been a highly successful anticancer drug in cancer therapy; however, its further application suffers severe nephrotoxicity. Herein, we identify bismuth tetraphenylporphyrinate [Bi(TPP)] as a potent protective agent against CDDP-induced nephrotoxicity. Bi(TPP) attenuates CDDP-induced acute kidney injury and prevents the death of mice exposed to a lethal dose of CDDP. The protective potency of bismuth porphyrin complexes could be optimized by varying lipophilic TPP ligands with ideal ClogP values of 8-14. Unexpectedly, Bi(TPP) exhibited a protective role via metallothionein-independent pathways, i.e., maintenance of redox homeostasis and energy supplement, elimination of accumulated platinum in the kidney, and inactivation of caspases cascade in apoptotic pathway. Significantly, Bi(TPP) does not compromise the antitumor activity of CDDP in the orthotopic tumor xenograft mouse model. These findings suggest that Bi(TPP) could be incorporated into current CDDP-based cancer therapy as a nephroprotective agent.

摘要

顺铂（CDDP）一直是癌症治疗中一种非常成功的抗癌药物；然而，其进一步应用受到严重肾毒性的困扰。在此，我们确定四苯基卟啉铋[Bi(TPP)]是一种有效的抗顺铂诱导肾毒性的保护剂。Bi(TPP)减轻顺铂诱导的急性肾损伤，并防止暴露于致死剂量顺铂的小鼠死亡。通过改变具有8 - 14理想ClogP值的亲脂性TPP配体，可以优化卟啉铋配合物的保护效力。出乎意料的是，Bi(TPP)通过不依赖金属硫蛋白的途径发挥保护作用，即维持氧化还原稳态和能量补充、消除肾脏中积累的铂以及使凋亡途径中的半胱天冬酶级联失活。值得注意的是，在原位肿瘤异种移植小鼠模型中，Bi(TPP)不会损害顺铂的抗肿瘤活性。这些发现表明，Bi(TPP)可以作为一种肾保护剂纳入当前基于顺铂的癌症治疗中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/1e3b194a0f01/gr7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/20989971517e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/10c3ff08761a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/dc0745d480cf/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/3d41802c6b10/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/0725573f5934/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/1e3b194a0f01/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/d2205edab604/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/9c820bedd529/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/20989971517e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/10c3ff08761a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/dc0745d480cf/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/3d41802c6b10/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/0725573f5934/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d0/7191608/1e3b194a0f01/gr7.jpg

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