A cisplatin conjugate with tumor cell specificity exhibits antitumor effects in renal cancer models.
A cisplatin conjugate with tumor cell specificity exhibits antitumor effects in renal cancer models.
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DOI：
10.1186/s12885-023-10878-3
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发表时间：
2023-06-02
期刊：
影响因子：
3.8
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Mrdenovic, Stefan;Wang, Yanping;Yin, Lijuan;Chu, Gina Chia-Yi;Ou, Yan;Lewis, Michael S.;Heffer, Marija;Posadas, Edwin M.;Zhau, Haiyen E.;Chung, Leland W. K.;Edderkaoui, Mouad;Pandol, Stephen J.;Wang, Ruoxiang;Zhang, Yi
透明细胞肾细胞癌（ccRCC）是最常见的肾癌类型，因其对化疗和小分子抑制剂靶向治疗的耐药性而臭名昭著。肿瘤的亚细胞靶向治疗有可能对阻断耐药产生实质性的效果。我们测试了耐药性是否可以通过使用DZ-CIS的亚细胞靶向癌症治疗来规避，DZ-CIS是肿瘤细胞特异性七甲川羰花青染料（HMCD）与顺铂（CIS）的化学缀合物，顺铂是一种由于频繁的肾毒性而在ccRCC治疗中使用有限的化疗药物。DZ-CIS以剂量依赖性方式对Caki-1、786-O、ACHN和SN 12 C人ccRCC细胞系和小鼠Renca细胞显示出杀细胞作用，并在实验小鼠模型中抑制ACHN和Renca肿瘤形成。值得注意的是，在荷瘤小鼠中，与CIS治疗的对照动物相比，重复使用DZ-CIS不会引起肾毒性。在ccRCC肿瘤中，DZ-CIS治疗抑制增殖标志物，但诱导细胞死亡标志物水平。此外，半数最大抑制浓度（IC 50）的DZ-CIS使Caki-1细胞对小分子mTOR抑制剂敏感。从机制上讲，DZ-CIS选择性地积累在ccRCC细胞的亚细胞器中，在那里它破坏线粒体的结构和功能，导致细胞色素C释放、半胱天冬酶激活和凋亡性癌细胞死亡。这项研究的结果强烈表明DZ-CIS是一种安全有效的亚细胞靶向癌症治疗方法。在线版本包含补充材料，可通过10.1186/s12885-023-10878-3获得。
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and is notorious for its resistance to both chemotherapy and small-molecule inhibitor targeted therapies. Subcellular targeted cancer therapy may thwart the resistance to produce a substantial effect. We tested whether the resistance can be circumvented by subcellular targeted cancer therapy with DZ-CIS, which is a chemical conjugate of the tumor-cell specific heptamethine carbocyanine dye (HMCD) with cisplatin (CIS), a chemotherapeutic drug with limited use in ccRCC treatment because of frequent renal toxicity. DZ-CIS displayed cytocidal effects on Caki-1, 786-O, ACHN, and SN12C human ccRCC cell lines and mouse Renca cells in a dose-dependent manner and inhibited ACHN and Renca tumor formation in experimental mouse models. Noticeably, in tumor-bearing mice, repeated DZ-CIS use did not cause renal toxicity, in contrast to the CIS-treated control animals. In ccRCC tumors, DZ-CIS treatment inhibited proliferation markers but induced cell death marker levels. In addition, DZ-CIS at half maximal inhibitory concentration (IC50) sensitized Caki-1 cells to small-molecule mTOR inhibitors. Mechanistically, DZ-CIS selectively accumulated in ccRCC cells’ subcellular organelles, where it damages the structure and function of mitochondria, leading to cytochrome C release, caspase activation, and apoptotic cancer cell death. Results from this study strongly suggest DZ-CIS be tested as a safe and effective subcellular targeted cancer therapy. The online version contains supplementary material available at 10.1186/s12885-023-10878-3.
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影响因子：
3.7
作者：
Hu P;Chu GC;Zhu G;Yang H;Luthringer D;Prins G;Habib F;Wang Y;Wang R;Chung LW;Zhau HE
通讯作者：
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作者：
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通讯作者：
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影响因子：
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作者：
Shi C;Wu JB;Chu GC;Li Q;Wang R;Zhang C;Zhang Y;Kim HL;Wang J;Zhau HE;Pan D;Chung LW
通讯作者：
Chung LW