Antiproliferative and proapoptotic effects of rapamycin and celecoxib in malignant melanoma cell lines.
Inhibitors of cyclooxygenase 2 (COX 2) and the mammalian target of rapamycin (mTOR) show direct and indirect antitumor effects in a variety of cancers. This study was designed to investigate the effects of the mTOR antagonist rapamycin and the COX 2 inhibitor celecoxib on cell growth and apoptosis in malignant melanoma. Cell proliferation was analysed by the cell proliferation ELISA BrdU and alamarBlue assay and apoptosis was measured by caspase 3 and 7 activity in two out of six melanoma cell lines (A375 and Mel Ho) that were selected for the heterogeneous levels of the COX 2 mRNA expression. The quantitative real-time reverse transcription polymerase chain reaction showed a 337-fold higher COX 2 mRNA level in the A375 than in the Mel Ho melanoma cells. However, both celecoxib and rapamycin caused significant growth inhibition in the two cell lines. By combining both agents, additive growth inhibitory effects were observed in the A375 cells. Treatment with celecoxib, but not rapamycin, increased apoptosis in the two cell lines. Our data indicate that rapamycin and celecoxib inhibit melanoma cell growth as single agents and a combination of both drugs have additive antitumor effects. Notably, the antiproliferative and proapoptotic effects of celecoxib seem to be independent of the COX 2 expression. Both rapamycin and celecoxib represent promising drugs for the palliative therapy of metastasised malignant melanoma and should be considered for future trials.
Bundscherer
Annika
A
Department of Dermatology, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, Germany.
Hafner
Christian
C
Maisch
Tim
T
Becker
Bernd
B
Landthaler
Michael
M
Vogt
Thomas
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D020123:Sirolimus