Progression and NSAID-induced apoptosis in malignant melanomas are independent of cyclooxygenase II.
Cyclooxygenase-II (Cox-II) overexpression is involved in the progression of various subtypes of cancer. We investigated the significance of Cox-II in the progression of malignant melanomas (MMs). Using immunohistology we determined that Cox-II is not expressed in 70 benign and malignant melanocytic tumours. Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) were also analysed as controls: the BCCs were consistently Cox-II negative (n = 11), whereas the SCCs showed moderate to strong Cox-II expression in 53% (n = 17). Reverse transcription-polymerase chain reaction and Western blotting of MM cell lines and MM tissues confirmed the lack of Cox-II expression in MM. However, in vitro the Cox-inhibiting non-steroidal anti-inflammatory drug (NSAID) sulindac sulphide (SIS) was significantly more effective in inducing apoptosis than sulindac sulphone (SOS), a derivative with a negligible effect on Cox (P < 0.01). The SIS doses needed for the induction of apoptosis were not significantly different in MM cell lines versus a Cox-II-positive colon carcinoma cell line (HT29). Furthermore, add-back experiments with high doses of the prostaglandins PGE2 and PGF2beta, major Cox-II products, did not abrogate this effect. We conclude that Cox-II expression is not involved in the progression of MM, and NSAID-induced apoptosis in MM cell lines seems to follow pathways independent of Cox-II. Nevertheless, Cox-II inhibitors are still candidates for therapy, though they act via an unknown mechanism.
Vogt
T
T
Department of Dermatology, University of Regensburg, D-93042 Regensburg, Germany. thomas.vogt@klinik.uni-regensburg.de
McClelland
M
M
Jung
B
B
Popova
S
S
Bogenrieder
T
T
Becker
B
B
Rumpler
G
G
Landthaler
M
M
Stolz
W
W
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002280:Basal Cell Carcinoma / Q000201:enzymology / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D002454:Cell Differentiation; D002648:Child; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D008565:Membrane Proteins; D008875:Middle Aged; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000201:enzymology / Q000473:pathology*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D013467:Sulindac; D012313:RNA; C025462:sulindac sulfide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C025463:sulindac sulfone