Katner Samantha J, Ginsburg Eric P, Hampton James D, Peterson Erica J, Koblinski Jennifer E, Farrell Nicholas P
Department of Biochemistry, Chemistry, and Geology, Minnesota State University, Mankato, Mankato, Minnesota 56001, United States.
Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia 23284, United States.
ACS Med Chem Lett. 2023 Sep 1;14(9):1224-1230. doi: 10.1021/acsmedchemlett.3c00244. eCollection 2023 Sep 14.
Heparan sulfate proteoglycans (HSPGs) and their associated proteins aid in tumor progression through modulation of biological events such as cell invasion, angiogenesis, metastasis, and immunological responses. Metalloshielding of the anionic heparan sulfate (HS) chains by cationic polynuclear platinum complexes (PPCs) prevents the HS from interacting with HS-associated proteins and thus diminishes the critical functions of HSPG. Studies herein exploring the PPC-HS interactions demonstrated that a series of PPCs varying in charge, nuclearity, distance between Pt centers, and hydrogen-bonding ability influence HS affinity. We report that the polyamine-linked complexes have high HS affinity and display excellent activity against breast cancer metastases and those arising in the bone and liver compared to carboplatin. Overall, the PPC-HS niche offers an attractive approach for targeting HSPG-expressing tumor cells.
硫酸乙酰肝素蛋白聚糖（HSPGs）及其相关蛋白通过调节细胞侵袭、血管生成、转移和免疫反应等生物学事件来促进肿瘤进展。阳离子多核铂配合物（PPCs）对阴离子硫酸乙酰肝素（HS）链的金属屏蔽作用可阻止HS与HS相关蛋白相互作用，从而削弱HSPG的关键功能。本文探索PPC-HS相互作用的研究表明，一系列在电荷、核数、铂中心之间的距离和氢键能力方面存在差异的PPCs会影响HS亲和力。我们报告称，与卡铂相比，多胺连接的配合物具有高HS亲和力，并且对乳腺癌转移以及骨和肝转移表现出优异的活性。总体而言，PPC-HS微环境为靶向表达HSPG的肿瘤细胞提供了一种有吸引力的方法。
