Novel dual cyclooxygenase and lipoxygenase inhibitors targeting hyaluronan–CD44v6 pathway and inducing cytotoxicity in colon cancer cells

Abstract

Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) enzyme have been found to play a role in promoting growth in colon cancer cell lines. The di-tert-butyl phenol class of compounds has been found to inhibit both COX-2 and 5-LOX enzymes with proven effectiveness in arresting tumor growth. In the present study, the structural analogs of 2, 6 di-tert-butyl-p-benzoquinone (BQ) appended with hydrazide side chain were found to inhibit COX-2 and 5-LOX enzymes at micromolar concentrations. Molecular docking of the compounds into COX-2 and 5-LOX protein cavities indicated strong binding interactions supporting the observed cytototoxicities. The signaling interaction between endogenous hyaluronan and CD44 has been shown to regulate COX-2 activities through ErbB2 receptor tyrosine kinase (RTK) activation. In the present studies it has been observed for the first time, that three of our COX/5-LOX dual inhibitors inhibit proliferation upon hydrazide substitution and prevent the activity of pro-angiogenic factors in HCA-7, HT-29, Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressed in colon cancer cells, through inhibition of the Hyaluronan/CD44v6 cell survival pathway. Since there is a substantial enhancement in the antiproliferative activities of these compounds upon hydrazide substitution, the present work opens up new opportunities for evolving novel active compounds of BQ series for inhibiting colon cancer.

Overexpression of c-Met and CD44v6 Receptors Contributes to Autocrine TGF-β1 Signaling in Interstitial Lung Disease

“…In contrast, CD44v6-containing isoforms were strongly suppressed ( Fig. 1H), which is in accordance with our previous CD44v6 shRNA results, both in vitro and in vivo (36,37,40,(42)(43)(44). , consistent with the immunofluorescence data in Fig.…”

Periostin Induces Intracellular Cross-talk between Kinases and Hyaluronan in Atrioventricular Valvulogenesis

“…Our findings in Figs. 1-12 lead to the hypothesis that PN INTEGRIN signaling pathways might be coordinately linked to HA signaling pathways through its adhesion receptor, CD44, for valve cell differentiation/maturation through collagen compaction and may be for collagen production as has been seen in our recent study in fibrogenic lung fibroblasts (19). This hypothesis is included in Fig.…”

“…The resulting pSicoR-PN shRNA (PN shRNA) transfectants constitutively silence PN genes in the cells. pSicoR-scrambled shRNA transfectants were used as controls as described previously (19,22,25,28).…”

Inhibition of lipoxygenase by sesamol corroborates its potential anti-inflammatory activity

“…Arachidonic acid is metabolized to potent inflammatory mediators -prostaglandins and leukotrienes. LOX metabolizes arachidonic acid to HETE and finally to leukotrienes, whereas, cyclooxygenase action on arachidonic acid results in the formation of prostaglandins [22]. A successful way of counteract the adverse effect of inflammation is blocking the production of inflammatory mediators.…”