Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
J Am Chem Soc. 2024 Aug 14;146(32):22530-22540. doi: 10.1021/jacs.4c06267. Epub 2024 Jul 31.
Cellular communication mediated by messenger molecules plays an important role in the progression of cancer. Herein, pH-sensitive zeolitic imidazolate framework-8 (ZIF-8) loaded with PtCl(OH)(NH) [i.e., Pt(IV)] bimetallic nanoplatforms were developed for prostate cancer therapy by interfering inositol-1, 4, 5-trisphosphate (IP3)-mediated cellular communication. As an important messenger in cells, the function of IP3 was found to be efficiently interfered with by the Pt(IV)-binding inositol unit. This finding effect of Pt(IV) is totally different from its traditional function as a prodrug of -platinum for chemotherapy. The decreased IP3 signal further downregulated the cytoplasmic Ca concentration and downstream signal transduction to inhibit proliferation and invasion of tumor cells. Meanwhile, Zn released from ZIF-8 under an acidic tumor microenvironment decreased adenosine triphosphate biosynthesis, which could further limit the cellular communication. Such a proposed strategy of interfering cellular communication has demonstrated its feasibility in this study, which may provide new perspectives for cancer therapy.
信使分子介导的细胞通讯在癌症的进展中起着重要作用。在此，通过干扰三磷酸肌醇（IP3）介导的细胞通讯，开发了负载 PtCl(OH)(NH)[即 Pt(IV)]双金属纳米平台的 pH 敏感沸石咪唑酯骨架-8（ZIF-8）用于前列腺癌治疗。作为细胞中的一种重要信使，发现 IP3 的功能可被 Pt(IV)结合的肌醇单元有效干扰。这种 Pt(IV)的发现效果与传统的作为化疗前药的 -铂的作用完全不同。减少的 IP3 信号进一步下调细胞质 Ca 浓度和下游信号转导，以抑制肿瘤细胞的增殖和侵袭。同时，在酸性肿瘤微环境下从 ZIF-8 中释放的 Zn 会减少三磷酸腺苷的生物合成，这进一步限制了细胞通讯。这种干扰细胞通讯的策略在本研究中证明了其可行性，这可能为癌症治疗提供新的视角。
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