Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, SK-841 04 Bratislava, Slovakia.
Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology in Bratislava, Radlinského 9, SK-812 37 Bratislava, Slovakia.
Int J Mol Sci. 2021 Aug 10;22(16):8608. doi: 10.3390/ijms22168608.
High levels of hyaluronic acid (HA) in tumors correlate with poor outcomes with several types of cancers due to HA-driven support of adhesion, migration and proliferation of cells. In this study we explored how to enhance the degradation of HA into low-molecular fragments, which cannot prevent the immune system to fight tumor proliferation and metastases. The physiological solution of HA was exposed to oxidative degradation by ascorbate and cupric ions in the presence of either one of three isomeric Mn(III) substituted -alkyl- and alkoxyalkylpyridylporphyrins or isomeric Mn(III) -methylpyridyl analog, commonly known as mimics of superoxide dismutase. The changes in hyaluronan degradation kinetics by four Mn(III) porphyrins were monitored by measuring the alteration in the dynamic viscosity of the HA solution. The compounds MnTE-2-PyP (BMX-010, AEOL10113), MnTnBuOE-2-PyP (BMX-001) and MnTnHex-2-PyP are able to redox cycle with ascorbate whereby producing HO which is subsequently coupled with Cu(I) to produce the OH radical essential for HA degradation. Conversely, with the analog, MnTM-4-PyP, no catalysis of HA degradation was demonstrated, due to its inertness towards redox cycling with ascorbate. The impact of different Mn(III)-porphyrins on the HA decay was further clarified by electron paramagnetic resonance spectrometry. The ability to catalyze the degradation of HA in a biological milieu, in the presence of cupric ions and ascorbate under the conditions of high tumor oxidative stress provides further insight into the anticancer potential of redox-active isomeric Mn(III) porphyrins.
肿瘤中透明质酸（HA）水平较高与几种癌症的不良预后相关，这是由于 HA 支持细胞的黏附、迁移和增殖。在这项研究中，我们探索了如何增强 HA 降解为低分子量片段，这些片段不能阻止免疫系统对抗肿瘤增殖和转移。在存在三种异构体 Mn(III)取代的 -烷基-和烷氧基烷基吡啶卟啉或异构体 Mn(III) -甲基吡啶类似物之一的情况下，HA 的生理溶液暴露于抗坏血酸和铜离子的氧化降解中，这些类似物通常被认为是超氧化物歧化酶的模拟物。通过测量 HA 溶液动态粘度的变化来监测四种 Mn(III)卟啉对透明质酸降解动力学的影响。化合物 MnTE-2-PyP（BMX-010，AEOL10113）、MnTnBuOE-2-PyP（BMX-001）和 MnTnHex-2-PyP 能够与抗坏血酸进行氧化还原循环，从而产生 HO，HO 随后与 Cu(I)偶联产生 OH 自由基，这是 HA 降解所必需的。相反，由于其对与抗坏血酸的氧化还原循环无反应性，MnTM-4-PyP 模拟物不能催化 HA 降解。电子顺磁共振波谱进一步阐明了不同 Mn(III)卟啉对 HA 衰减的影响。在高肿瘤氧化应激条件下，在铜离子和抗坏血酸存在下，在生物环境中催化 HA 降解的能力为氧化还原活性异构体 Mn(III)卟啉的抗癌潜力提供了进一步的认识。
