AI Article Synopsis

  • - Alkaline phosphatases (APs) are enzymes that have a role in various diseases, including cancer and Alzheimer's, and their overexpression is linked to disease progression.
  • - The study tested three COX-2 inhibitors—nimesulide, piroxicam, and lornoxicam—for their ability to inhibit APs, finding nimesulide showed the most promise with strong binding and stability against the tissue nonspecific alkaline phosphatase (TNAP).
  • - In laboratory tests, nimesulide and the other COX-2 inhibitors significantly reduced the activity of alkaline phosphatases in cancer cell lines, suggesting potential for these inhibitors in developing new cancer treatments.

Article Abstract

Alkaline phosphatases (APs, EC 3.1.3.1) belong to a superfamily of biological macromolecules that dephosphorylate many phosphometabolites and phosphoproteins and their overexpression is intricated in the spread of cancer to liver and bones, neuronal disorders including Alzheimer's disease (AD), inflammation and others. It was hypothesized that cyclooxygenase-2 (COX-2) selective inhibitors may possess anti-APs potential and may be involved in anticancer proceedings. Three COX-2 inhibitors including nimesulide, piroxicam and lornoxicam were evaluated for the inhibition of APs using in silico and in vitro methods. Molecular docking studies against tissue nonspecific alkaline phosphatase (TNAP) offered the best binding affinities for nimesulide (-11.14 kcal/mol) supported with conventional hydrogen bonding and hydrophobic interactions. MD simulations against TNAP for 200 ns and principal component analysis (PCA) reiterated the stability of ligand-receptor complexes. Molecular expression analysis of TNAP enzyme in the breast cancer cell line MCF-7 exhibited 0.24-fold downregulation with 5 μM nimesulide as compared with 0.26-fold standard 10 μM levamisole. In vitro assays against human placental AP (hPAP) displayed potent inhibitions of these drugs with IC values of 0.52 ± 0.02 μM to 3.46 ± 0.13 μM and similar results were obtained for bovine intestinal AP (bIAP). The data when generalized collectively emphasizes that the inhibition of APs by COX-2 inhibitors provides another target to work on the development of anticancer drugs.

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http://dx.doi.org/10.1016/j.ijbiomac.2024.132721DOI Listing

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