TY - JOUR
T1 - Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo
AU - Eli, Yaniv
AU - Przedecki, Fiorenza
AU - Levin, Galit
AU - Kariv, Na'am
AU - Raz, Amiram
N1 - Funding Information:
This study was supported in part by the Ela Kodesz Institute for Research on Cancer Development and Prevention and by the N. Singer Foundation of Tel Aviv University.
PY - 2001/3/1
Y1 - 2001/3/1
N2 - Considerable research effort is currently being directed towards understanding the mechanisms mediating the antiproliferative effects of non-steroidal anti-inflammatory drugs (NSAIDs) and, more recently, of cyclooxygenase (COX)-2 inhibitors as well. A key question is whether NSAIDs (excluding sulindac) exert their anticarcinogenic effects in vivo by a mechanism that is dependent on their capacity to inhibit COX activity. Some studies with cultured tumor cells in vitro have argued against such a linkage, showing that NSAIDs inhibit cell replication and/or augment apoptosis only at concentrations that exceed those required to inhibit COX activities 10- to 100-fold. The significance of these results for the observed anticarcinogenic effects of NSAIDs in vivo has not yet been evaluated. We addressed this question by comparing, for the same tumor cells, the effects of the NSAID indomethacin on cell growth parameters when the cells were grown in culture to the effects seen in the in vivo growing tumor in the mouse. Indomethacin added to cultured Lewis lung carcinoma cells exerted a potent antiproliferative effect (3H thymidine assay) and reduced cell viability (MTT[3-(4,5-dimethyl(thiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay) at low doses (10-20 μM) in parallel with its inhibitory effect on cellular cyclooxygenase. These effects of indomethacin appeared to arise from a clear antiproliferative shift in the profile of the cell cycle parameters towards a reduced percentage of cells at the S and G2/M phases, together with an increased percentage of cells at the G1 phase. Significantly, similar results were seen when indomethacin was given in vivo at the low dose of 2 mg per kg/day, which blocked blood platelet COX activity and at the same time produced a delay in tumor growth initiation and attenuation of apparent primary tumor growth as well as growth of lung metastases. These results thus provide strong support for the notion that COX inhibition is a major determinant in the antitumorigenic effect of indomethacin in vivo.
AB - Considerable research effort is currently being directed towards understanding the mechanisms mediating the antiproliferative effects of non-steroidal anti-inflammatory drugs (NSAIDs) and, more recently, of cyclooxygenase (COX)-2 inhibitors as well. A key question is whether NSAIDs (excluding sulindac) exert their anticarcinogenic effects in vivo by a mechanism that is dependent on their capacity to inhibit COX activity. Some studies with cultured tumor cells in vitro have argued against such a linkage, showing that NSAIDs inhibit cell replication and/or augment apoptosis only at concentrations that exceed those required to inhibit COX activities 10- to 100-fold. The significance of these results for the observed anticarcinogenic effects of NSAIDs in vivo has not yet been evaluated. We addressed this question by comparing, for the same tumor cells, the effects of the NSAID indomethacin on cell growth parameters when the cells were grown in culture to the effects seen in the in vivo growing tumor in the mouse. Indomethacin added to cultured Lewis lung carcinoma cells exerted a potent antiproliferative effect (3H thymidine assay) and reduced cell viability (MTT[3-(4,5-dimethyl(thiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay) at low doses (10-20 μM) in parallel with its inhibitory effect on cellular cyclooxygenase. These effects of indomethacin appeared to arise from a clear antiproliferative shift in the profile of the cell cycle parameters towards a reduced percentage of cells at the S and G2/M phases, together with an increased percentage of cells at the G1 phase. Significantly, similar results were seen when indomethacin was given in vivo at the low dose of 2 mg per kg/day, which blocked blood platelet COX activity and at the same time produced a delay in tumor growth initiation and attenuation of apparent primary tumor growth as well as growth of lung metastases. These results thus provide strong support for the notion that COX inhibition is a major determinant in the antitumorigenic effect of indomethacin in vivo.
KW - Cell cycle
KW - Cell proliferation
KW - Cyclooxygenases
KW - Indomethacin
KW - NSAIDs
KW - Tumor cells
UR - http://www.scopus.com/inward/record.url?scp=0035282655&partnerID=8YFLogxK
U2 - 10.1016/S0006-2952(00)00578-5
DO - 10.1016/S0006-2952(00)00578-5
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:0035282655
SN - 0006-2952
VL - 61
SP - 565
EP - 571
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 5
ER -
