Small molecule inhibition of DDAH1 significantly attenuates triple negative breast cancer cell vasculogenic mimicry in vitro - 16/02/19
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Graphical abstract |
Highlights |
• | Intracellular ZST316 and ZST152 can be quantified using a sensitive UPLC-MS assay. |
• | ZST316 and ZST152 inhibit DDAH1 activity in MDA-MB-231 breast cancer cells. |
• | DDAH1 inhibition by ZST316 or ZST152 increases intracellular ADMA concentrations. |
• | DDAH1 inhibition by ZST316 or ZST152 decreases intracellular l-citrulline concentrations. |
• | ZST316 and ZST152 significantly inhibit MDA-MB-231 cell migration and VM. |
Abstract |
Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a key enzyme involved in the metabolism of the endogenous nitric oxide synthase (NOS) inhibitors asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA). Increased DDAH1 expression and subsequent increased NO production have been recently linked to cancer. Specifically, DDAH1 is implicated in establishment of a vascular network by tumour cells, vasculogenic mimicry (VM), which is strongly associated with tumour progression and poor patient prognosis. The use of DDAH1 inhibitors as potential therapeutic agents thus represents a growing field of interest. Here we describe a UPLC-MS assay to quantify stability and intracellular concentration of two small molecule DDAH1 inhibitors synthesised by our group, ZST316 and ZST152, following incubation with MDA-MB-231 breast cancer cells. In an in vitro assay of VM, both DDAH1 inhibitors significantly attenuated formation of capillary-like tube structures in a dose-dependent fashion. This was not due to cell toxicity or altered cell proliferation, but may be due in part to inhibition of cell migration. Mechanistically, we demonstrate significant modulation of the endogenous DDAH/ADMA/NO pathway following exposure of 100 μM ZST316 or ZST152: a 40% increase in the DDAH1 substrate ADMA, and a 38% decrease in the DDAH1 product l-citrulline. This study represents the first evidence for therapeutic inhibition of DDAH1 by small molecules in breast cancer.
Le texte complet de cet article est disponible en PDF.Keywords : DDAH1, Nitric oxide, Vasculogenic mimicry, Breast cancer, ADMA
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Vol 111
P. 602-612 - mars 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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