Celecoxib antagonizes perifosine's anticancer activity involving a cyclooxygenase-2-dependent mechanism

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Perifosine is an orally bioavailable alkylphospholipid investigated as an anticancer agent.
• Its mechanism of action in human cancer cells is under active investigation.

Purpose of the Study:

• To elucidate a novel anticancer mechanism of perifosine involving cyclooxygenase 2 (COX-2).
• To investigate the role of COX-2 induction in perifosine's efficacy against lung and head and neck cancers.

Main Methods:

• Assessed perifosine's effects on apoptosis and cell cycle arrest in cancer cell lines.
• Examined perifosine-induced changes in COX-2 expression and activity.
• Utilized antisense and small interfering RNA (siRNA) to block COX-2 induction.
• Evaluated drug interactions in cell culture and lung cancer xenograft models.

Main Results:

• Perifosine induced apoptosis and cell cycle arrest in lung and head and neck cancer cell lines.
• Perifosine treatment rapidly and potently increased COX-2 levels and activity, correlating with growth inhibition.
• Blocking COX-2 induction reduced cancer cell sensitivity to perifosine.
• Combination of perifosine with celecoxib decreased sensitivity in vitro and in vivo.

Conclusions:

• Cyclooxygenase 2 (COX-2) activation is a key mechanism contributing to perifosine's anticancer activity, including apoptosis and growth arrest.
• The findings suggest a potential drug contradiction when combining perifosine with COX-2 inhibitors like celecoxib.
• These results have clinical relevance for optimizing cancer therapy regimens involving perifosine.