Mitochondria-Targeted Titanium Complex Exerts Potent Anticancer Activity by Disturbing Iron Homeostasis.

IF 4.9 Q1 CHEMISTRY, MEDICINAL

ACS Pharmacology and Translational Science Pub Date : 2025-05-29 eCollection Date: 2025-06-13 DOI:10.1021/acsptsci.5c00219

Qi-Xin Guan, Long-Bo Yu, Peng Wang, Qing-Yuan Hu, Cai-Ping Tan

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引用次数: 0

Abstract

Triple-negative breast cancer (TNBC) is an aggressive malignancy, with limited targeted treatment options. In this study, we developed a novel triphenylphosphine (TPP)-modified deferasirox (DFX) titanium complex (Ti-DFX-TPP) to disrupt iron homeostasis in TNBC cells through transmetalation. Ti-DFX-TPP depletes the labile iron pool, triggering a compensatory upregulation of transferrin receptor 1 (TfR1) in response to an intracellular iron deficiency. The disruption of iron metabolism by Ti-DFX-TPP increases reactive oxygen species (ROS) levels, which in turn lead to mitochondrial dysfunction and DNA damage, ultimately inhibiting cancer cell growth. In vivo studies further demonstrated that Ti-DFX-TPP inhibits tumor growth without significant toxicity to major organs. These findings suggest that Ti-DFX-TPP is a promising therapeutic candidate for TNBC, as it exploits the disruption of iron metabolism and ROS pathways to enhance its anticancer efficacy.

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线粒体靶向钛复合物通过扰乱铁稳态发挥有效的抗癌活性。

三阴性乳腺癌（TNBC）是一种侵袭性恶性肿瘤，具有有限的靶向治疗选择。在这项研究中，我们开发了一种新的三苯基膦（TPP）修饰的去铁酸铁（DFX）钛配合物（Ti-DFX-TPP），通过金属转化破坏TNBC细胞中的铁稳态。Ti-DFX-TPP会耗尽不稳定的铁池，引发转铁蛋白受体1 （TfR1）的代偿性上调，以应对细胞内铁缺乏。Ti-DFX-TPP破坏铁代谢，增加活性氧（ROS）水平，进而导致线粒体功能障碍和DNA损伤，最终抑制癌细胞生长。体内研究进一步证明Ti-DFX-TPP抑制肿瘤生长，对主要器官无明显毒性。这些发现表明，Ti-DFX-TPP是一种很有前景的TNBC治疗候选药物，因为它利用铁代谢和ROS通路的破坏来增强其抗癌功效。

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来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

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