Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Cyclooxygenase-2 (COX-2) inhibitors demonstrate antitumor properties, but their precise mechanisms remain unclear.
• Apricoxib is an investigational COX-2 inhibitor with potential therapeutic applications.
• Understanding apricoxib's action in colorectal carcinoma is crucial for its clinical development.

Purpose of the Study:

• To elucidate the mechanisms of action of apricoxib in HT29 colorectal carcinoma.
• To investigate the impact of apricoxib on tumor cell proliferation, apoptosis, and angiogenesis.
• To determine the role of epithelial-mesenchymal transition (EMT) in apricoxib's antitumor efficacy.

Main Methods:

• In vitro cytotoxicity assays and in vivo tumor growth inhibition studies in HT29 colorectal carcinoma models.
• Pharmacokinetic analysis to determine drug concentrations and prostaglandin E(2) inhibition.
• Assessment of tumor cell proliferation, apoptosis, vascularization, and epithelial-mesenchymal transition (EMT) markers (E-cadherin, vimentin, ZEB1).

Main Results:

• Apricoxib exhibited weak in vitro cytotoxicity but significant in vivo tumor growth inhibition.
• In vivo drug levels achieved complete prostaglandin E(2) inhibition but were below cytotoxic concentrations in vitro.
• Apricoxib treatment inhibited proliferation, induced apoptosis, promoted vascular normalization, and reversed EMT by upregulating E-cadherin and downregulating vimentin and ZEB1.
• In vitro, anchorage-independent growth or forced EMT sensitized cancer cells to apricoxib.

Conclusions:

• Apricoxib demonstrates significant single-agent antitumor activity in colorectal carcinoma.
• The acquisition of mesenchymal characteristics through EMT sensitizes carcinoma cells to apricoxib.
• EMT reversal is a key mechanism underlying apricoxib's efficacy, suggesting a potential therapeutic strategy for COX-2-dependent cancers.