Celecoxib Antagonizes Perifosine's Anticancer Activity Involving a Cyclooxygenase-2-Dependent Mechanism

• Type of Material: Article
• Authors: Heath A. Elrod, Emory University; Ping Yue, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2009-09
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 American Association for Cancer Research
• Final Published Version (URL): http://mct.aacrjournals.org/content/8/9/2575
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• ISSN: 1535-7163
• Volume: 8
• Issue: 9
• Start Page: 2575
• End Page: 2585
• Grant/Funding Information: The Georgia Cancer Coalition Distinguished Cancer Scholar award (S-Y. S), Department of Defense grants W81XWH-04-1-0142-VITAL (S-Y. Sun for Project 4), National Cancer Institute SPORE P50 grant CA128613-01 (S-Y. Sun for Project 2), and American Cancer Society Postdoctoral Fellowship PF-07-033-01-CCG (H.A. Elrod).
• Keywords: cyclooxygenase-2; celecoxib; Perifosine; apoptosis
• Research Categories: Health Sciences, Oncology

Abstract

Perifosine is an orally bioavailable alkylphospholipid currently being tested in Phase II clinical trials as a potential anticancer drug. In this study, we have revealed a novel mechanism underlying perifosine's anticancer activity involving induction of cyclooxygenase 2 (COX-2) in human cancer cells. Perifosine induced apoptosis and/or cell cycle arrest in several lung and head and neck cancer cell lines. However, the combination of perifosine with low concentrations of celecoxib rendered cells less sensitive to perifosine both in cell culture systems and in lung cancer xenograft models. Subsequently, we examined the effects of perifosine on COX-2 expression and activity in a set of lung and head and neck cancer cell lines and found that perifosine rapidly and potently increased COX-2 levels and activity, the degrees of which correlated to perifosine's abilities to inhibit the growth of cancer cells. We also detected increased COX-2 levels in lung cancer xenografts treated with perifosine. Moreover, blockage of COX-2 induction by both antisense and siRNA approaches decreased cell sensitivity to perifosine. Collectively, these data indicate that the activation of COX-2 contributes to perifosine's anticancer activity including apoptosis induction and growth arrest. These data are clinically relevant as they suggest that the combination of perifosine and COX-2 inhibitors such as celecoxib, may produce a potential drug contradiction.