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 It was withdrawn from the market after the demonstration of an increased risk of cardiovascular complications after prolonged use.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 this 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, 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 signaling 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.

• Authors: Claudia Bocca, Francesca Bozzo, Monica Ievolella, Antonella Miglietta
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 361 Issue 1-2 Pg. 105-10 (Feb 2012) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 22002318 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cadherins
• Cyclooxygenase 2 Inhibitors
• MYC protein, human
• NO-rofe
• Nitrates
• Proto-Oncogene Proteins c-myc
• beta Catenin
• Cyclooxygenase 2
• Mitogen-Activated Protein Kinases
• 4-Butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, pharmacology)
• Antineoplastic Agents (pharmacology)
• Cadherins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Humans
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Nitrates (pharmacology)
• Phosphorylation
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• beta Catenin (genetics, metabolism)