Inhibition of COX activity by NSAIDs or ascorbate increases cAMP levels and enhances differentiation in 1α,25-dihydroxyvitamin D3-induced HL-60 cells

Arachidonic acid metabolism is modulated during differentiation induced by 1α,25(OH)2D3 in HL-60 cells. Antioxidants that affect arachidonic acid metabolism enhance this differentiation program. Ascorbate also enhances differentiation in 1α,25(OH)2D3-induced cells depending on the induction of cAMP. The aim of this work was to study if this cAMP rise depends on modulation of arachidonic acid metabolism by ascorbate. Cyclooxygenase inhibitors, indomethacin and aspirin, increased cAMP levels and also enhanced 1α,25(OH)2D3-induced differentiation in HL-60 cells. Ascorbate did not affect the release of arachidonic acid-derived metabolites but decreased the levels of TXB2 and PGE2, suggesting the inhibition of cyclooxygenase. On the other hand, free arachidonic acid increased both cAMP levels and differentiation in the absence or presence of 1α,25(OH)2D3. Neither cyclooxygenase inhibitors nor ascorbate modified AA effect. Then, inhibition of cyclooxygenase activity by ascorbate could accumulate free arachidonic acid or other metabolites that increase cAMP levels and enhance differentiation in 1α,25(OH)2D3-induced HL-60 cells.