释放CO的分子和NO供体对细胞生物能的调节可抑制癌细胞与人肺微血管内皮细胞的相互作用。,Pharmacological Research

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释放CO的分子和NO供体对细胞生物能的调节可抑制癌细胞与人肺微血管内皮细胞的相互作用。
Pharmacological Research ( IF 9.1 ) Pub Date : 2018-09-10 , DOI: 10.1016/j.phrs.2018.09.005
Marta Stojak ₁ , Patrycja Kaczara ₁ , Roberto Motterlini ₂ , Stefan Chlopicki ₃

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癌细胞与内皮细胞之间的相互作用在转移过程中起着至关重要的作用。在这里，我们检查了单独或组合使用的一氧化碳释放分子（CORM-401）和一氧化氮供体（PAPA NONOate）对乳腺癌细胞粘附和跨肺微血管内皮转运的影响。我们进一步探讨了CO和NO对癌症-内皮细胞相互作用的影响是否与乳腺癌或内皮细胞中细胞生物能的变化有关。我们发现，单独或组合使用CORM-401和PAPA NONOate可以显着减少乳腺癌细胞跨人肺微血管内皮细胞（hLMVEC）的迁移，而仅通过两种化合物的组合可以减少癌细胞对内皮的粘附。在hLMVEC中，CORM-401减少糖酵解并刺激线粒体呼吸，而在乳腺癌细胞中，CORM-401减少糖酵解和线粒体呼吸。相反，PAPA NONOate降低了两种细胞系中的线粒体呼吸作用并轻微刺激了糖酵解。当两个供体一起给予时，线粒体的呼吸作用和糖酵解作用都被深深地抑制，癌症-内皮细胞的相互作用被相加地抑制。当单独应用时，参与乳腺癌细胞与hLMVEC粘附的细胞间粘附分子1（ICAM-1）被CORM-401和PAPA NONOate下调，而两种化合物的组合均未引起ICAM-1下调的任何增强。结论，我们的发现表明，一氧化碳和一氧化氮对癌症和内皮细胞的细胞生物能有不同的影响，并表明这种现象可能有助于一氧化碳和一氧化氮的加和抗粘连和反迁移作用。代谢的药理学衰减代表了一种防止癌细胞与内皮相互作用的新颖，有效的方法，这是一种耗能的过程。

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Modulation of cellular bioenergetics by CO-releasing molecules and NO-donors inhibits the interaction of cancer cells with human lung microvascular endothelial cells.

Interactions between cancer cells and the endothelium play a crucial role during metastasis. Here we examined the effects of a carbon monoxide-releasing molecule (CORM-401) and a nitric oxide donor (PAPA NONOate) given alone or in combination on breast cancer cell adhesion and transmigration across the lung microvascular endothelium. We further explored whether the effects of CO and NO on cancer-endothelial cells interactions are linked with changes in cellular bioenergetics in breast cancer or endothelial cells. We found that CORM-401 and PAPA NONOate alone or in combination markedly decreased transmigration of breast cancer cells across human lung microvascular endothelial cells (hLMVEC), while cancer cell adhesion to the endothelium was diminished only by a combination of the two compounds. In hLMVECs, CORM-401 decreased glycolysis and stimulated mitochondrial respiration, while in breast cancer cells CORM-401 decreased both glycolysis and mitochondrial respiration. In contrast, PAPA NONOate decreased mitochondrial respiration and slightly stimulated glycolysis in both cell lines. When both donors were given together, mitochondrial respiration and glycolysis were both profoundly inhibited, and cancer-endothelial cells interactions were additively suppressed. Intercellular adhesion molecule-1 (ICAM-1), involved in breast cancer cell adhesion to hLMVECs, was downregulated by CORM-401 and PAPA NONOate, when applied alone, while a combination of both compounds did not cause any enhancement of ICAM-1 downregulation. In conclusion, our findings demonstrate that CO and NO differently affect cellular bioenergetics of cancer and endothelial cells and suggest that this phenomenon may contribute to additive anti-adhesive and anti-transmigratory effects of CO and NO. Pharmacological attenuation of metabolism represents a novel, effective way to prevent cancer cell interactions with the endothelium, that is an energy-demanding process.

更新日期：2019-11-01

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