1.In silico and In vitro evaluation of the anti-inflammatory potential of Centratherum punctatum Cass-A.
Shankaran S K1, Ganai SA1,2, Kp A3, Brindha P3, Mahadevan V1,2. J Biomol Struct Dyn. 2016 Mar 16:1-30. [Epub ahead of print]
Centratherum punctatum Cass, a herb belonging to the family Asteraceae has been traditionally used as a curative against diverse disorders like inflammation, tumour, depression and hypertension. Though the medicinal properties of this plant have been attributed to the presence of flavonoids, glucosides, alkaloids, Vitamin C, etc, the molecular constituents of this plant and of the flavonoids that contribute to its medicinal activity have not been explored yet. This work attempts to evaluate the potential of Centratherum punctatum extract as an anti inflammatory agent. Ethanolic extracts of Centratherum punctatum analysed by High Performance Thin Layer Chromatography (HPTLC) and Liquid Chromatography - Mass Spectrometry (LC-MS/MS) identified the presence of the flavones kaempferol, glycoside Isorhamnetin-3-O-rutinoside and kaempferol-3-glucoside. The plant extract exhibited antioxidant property as confirmed by DPPH assay and IC50 value of 271.
2.Deciphering the mechanism behind the varied binding activities of COXIBs through Molecular Dynamic Simulations, MM-PBSA binding energy calculations and per-residue energy decomposition studies.
Chaudhary N1, Aparoy P1. J Biomol Struct Dyn. 2016 Apr 4:1-15. [Epub ahead of print]
COX-2 is a well-known drug target in inflammatory disorders. COX-1/COX-2 selectivity of NSAIDs is crucial in assessing the gastrointestinal side effects associated with COX-1 inhibition. Celecoxib, rofecoxib, and valdecoxib are well-known specific COX-2 inhibiting drugs. Recently, polmacoxib, a COX-2/CA-II dual inhibitor has been approved by the Korean FDA. These COXIBs have similar structure with diverse activity range. Present study focuses on unraveling the mechanism behind the 10-fold difference in the activities of these sulfonamide-containing COXIBs. In order to obtain insights into their binding with COX-2 at molecular level, molecular dynamics simulations studies, and MM-PBSA approaches were employed. Further, per-residue decomposition of these energies led to the identification of crucial amino acids and interactions contributing to the differential binding of COXIBs. The results clearly indicated that Leu338, Ser339, Arg499, Ile503, Phe504, Val509, and Ser516 (Leu352, Ser353, Arg513, Ile517, Phe518, Val523, and Ser530 in PGHS-1 numbering) were imperative in determining the activity of these COXIBs.
3.Dual Cyclooxygenase and Carbonic Anhydrase Inhibition by Nonsteroidal Anti-Inflammatory Drugs for the Treatment of Cancer.
De Monte C1, Carradori S, Gentili A, Mollica A, Trisciuoglio D, Supuran CT. Curr Med Chem. 2015;22(24):2812-8.
Among the class of nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors or "coxibs" selectively inhibit the activity of the inducible isoform of cyclooxygenase. Moreover, there is emerging evidence that the sulfonamide-type coxibs, but not the methylsulfones, display an inhibitory activity also against several isoforms of human carbonic anhydrase (CA, EC 18.104.22.168). In this regard, celecoxib and valdecoxib, possessing a primary sulfonamide that binds to the zinc ion at the active site of the enzyme, are nanomolar inhibitors of the cancer-related hCA IX isoform. Also meloxicam and lornoxicam, NSAIDs belonging to the class of "oxicams", that contain a cyclic tertiary sulfonamide moiety, inhibit this isoform at low micromolar concentrations. The multiple pharmacological effects of the sulfonamide anti-inflammatory agents could be ascribed to the dual inhibition of CA and COX enzymes, supporting the evidence that inflammation and hypoxia pathways are involved in cancer onset and progression and suggesting that the antitumoral activity of these compounds should be further explored for their possible use in the polypharmacology of cancer prevention and therapy.
4.Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1.
Schellhorn M1, Haustein M1, Frank M2, Linnebacher M3, Hinz B1. Oncotarget. 2015 Nov 17;6(36):39342-56. doi: 10.18632/oncotarget.5745.
The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study investigates the impact of celecoxib on the expression of intercellular adhesion molecule 1 (ICAM-1) and cancer cell lysis by lymphokine-activated killer (LAK) cells. Celecoxib, but not other structurally related selective COX-2 inhibitors (i.e., etoricoxib, rofecoxib, valdecoxib), was found to cause a substantial upregulation of ICAM-1 protein levels. Likewise, ICAM-1 mRNA expression was increased by celecoxib. Celecoxib enhanced the susceptibility of cancer cells to be lysed by LAK cells with the respective effect being reversed by a neutralizing ICAM-1 antibody. In addition, enhanced killing of celecoxib-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen 1 (LFA-1), suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process.