Antiproliferative and proapoptotic effects of rapamycin and celecoxib in malignant melanoma cell lines

Abstract

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.

Oral acetylsalicylic acid and prevalence of actinic keratosis

“…39 Additionally, celecoxib inhibited the growth of melanoma cells, even in strains not expressing COX-2. 40 There was a lower risk of SCC (OR=0.2) and a lower AK count (OR=0.5) among regular users of AINEs for more than one year, even in low doses. 41 Similar results concerning SCC were found in a population study with 1.484 participants, observing a risk reduction with various AINEs, mainly ASA, and more strongly for tumors positive for p53 or with a loss of heterozygosity of the PTCH gene.…”

Cathepsin-k expression in pulmonary lymphangioleiomyomatosis

“…29 MITF and cathepsin-k are also expressed in melanocytes and melanomas, 30 where mTOR is also activated and critical for the regulation of apoptosis. 31,32 All these data taken together, it is possible to hypothesize that MITF and cathepsink are in fact under the control of mTOR pathway, and could serve as further molecular markers for evaluating mTOR pathway activation in lymphangioleiomyomatosis. As there are no data regarding cathepsin-k expression in lymphangioleiomyomatosis currently available, we investigated in this study the expression of cathepsin-k in lymphangioleiomyomatosis and angiomyolipomas by using immunohistochemistry.…”

Angiogenesis in cutaneous disease: Part II

“…36 Sirolimus was shown to inhibit the proliferation of MM cell lines, especially when combined with celecoxib, a cyclooxygenase 2 inhibitor. 37 Combined treatment of six melanoma cell lines with sorafenib and sirolimus led to an approximately twofold increase of cell death compared with sorafenib alone. 38 A study using human melanoma xenotransplants in mice did not show a significant antitumor effect from temsirolimus alone; however, temsirolimus in combination with dacarbazine reduced tumor weight compared to dacarbazine monotherapy.…”