Celecoxib antagonizes perifosine's anticancer activity involving a cyclooxygenase-2-dependent mechanism.
Perifosine is an orally bioavailable alkylphospholipid currently being tested in phase II clinical trials as a potential anticancer drug. In this study, we reveal a novel mechanism underlying the anticancer activity of perifosine that involves the 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 the abilities of perifosine 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 small interfering RNA approaches decreased cell sensitivity to perifosine. Collectively, these data indicate that the activation of COX-2 contributes to the anticancer activity of perifosine, 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.
Elrod
Heath A
HA
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Yue
Ping
P
Khuri
Fadlo R
FR
Sun
Shi-Yong
SY
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D001483:Base Sequence; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D010767:Phosphorylcholine; C105905:perifosine; D051546:Cyclooxygenase 2; D000068579:Celecoxib