2-Methoxy-5-amino-N-hydroxybenzamide, a derivative of mesalamine, inhibits colon cancer cell growth through cyclo-oxygenase-2-dependent and -independent mechanisms

COX-2 (cyclo-oxygenase-2) and PGE₂ (prostaglandin E₂) play a key role in sustaining CRC (colorectal cancer) cell growth and survival. Indeed, the use of agents targeting the COX-2/PGE₂ axis has been associated with a reduction in the development of CRC in both humans and murine models of colon carcinogenesis. In the present study, we investigated whether 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a derivative of mesalamine that inhibits CRC cell growth both in vitro and in vivo, negatively regulates COX-2/PGE₂ expression in CRC cells and assessed whether the 2-14-mediated anti-neoplastic effect is strictly dependent on the inhibition of this pathway. Our results show that 2-14 blocks the growth and enhances the death of HT-115, a CRC cell line overexpressing COX-2, and that these effects associate with inhibition of COX-2 but not COX-1. 2-14 also down-regulates TNFα (tumour necrosis factor α)-induced COX-2 in HT-29 cells as well as COX-2/PGE₂ expression in ex vivo cultures of human CRC explants. Similarly, 2-14 reduces COX-2, but not COX-1, in tumoural areas developing in a mouse model of CAC (colitis-associated colon cancer). Finally, we show that 2-14 exhibits in vitro and in vivo anti-mitogenic effects in DLD-1, a COX-deficient CRC cell line. Taken together, these results suggest that 2-14 inhibits CRC cell growth through COX-2-dependent and -independent mechanisms.