A novel nitro-oxy substituted analogue of rofecoxib reduces human colon cancer cell growth

Abstract

Rofecoxib is a specific COX-2 inhibitor able to exert antiproliferative activity against colorectal cancer cells. It was withdrawn from the market after the demonstration of an increased risk of cardiovascular complications after prolonged use. Nevertheless it remains an interesting compound for laboratory research as an experimental COX-2 inhibitor. In the present study the antiproliferative activity of a novel dinitro-oxy-substituted analogue of rofecoxib (NO-rofe), potentially less cardiotoxic, has been investigated in vitro on human colon cancer cells and compared with the action of the parent drug. Due to the fact that COX-2 inhibition is the main characteristic of coxibs we performed all experiments in COX-2-overexpressing (HT-29) and COX-2-negative (SW-480) human colon cancer cells, in order to elucidate whether the observed effects were dependent on COX-2 inhibition. Moreover, experiments were performed in order to evaluate whether COX-2 pharmacological inhibition may affect beta-catenin/E-cadherin signalling pathway.NO-rofe exerted a significant antiproliferative activity on COX-2 positive HT-29 human colon cancer cells, being less effective on the COX-2 negative SW-480 human colon cancer cell line. In particular, the rofecoxib analogue retained similar potencies with respect to COX-2 inhibition but was much more active than rofecoxib in inhibiting the growth of human colon cancer cells in vitro.In addition, this novel compound resulted in the induction of membrane β-catenin/E-cadherin expression, a feature that may significantly contribute to its antiproliferative activity.

Valdecoxib Recovers the Lipid Composition, Order and Dynamics in Colon Cancer Cell Lines Independent of COX-2 Expression: An ATR-FTIR Spectroscopy Study

“…10,12 Nevertheless, they remain interesting compounds for laboratory research as experimental COX-2 inhibitors. 11,[13][14][15][16] Furthermore, CLX has also been approved by the U.S. Food and Drug Administration (FDA) for use as a chemopreventive agent for patients with familial adenomatous polyposis (FAP). 4 Valdecoxib is a diaryl substituted isoxazole, structurally similar to CLX.…”

Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells

“…Therefore, carboranyl analogues with different substituents at this position, including a nitrate moiety as in previously reported NO-releasing rofecoxib prodrugs, were synthesized ( Fig. 1) 25 .…”

“…Bocca et al showed that a dinitrate-modified rofecoxib analogue (Fig. 1) had a stronger antiproliferative activity against COX-2-positive HT-29 human colon cancer cells than COX-2-negative SW-480 human colon cancer cells 25 . They demonstrated that, even though COX-2 was inhibited with similar potency, the antitumor potential of the inhibitor was amplified as a consequence of the nitrate modification.…”