Interaction between celecoxib and docetaxel or cisplatin in human cell lines of ovarian cancer and colon cancer is independent of COX-2 expression levels.
Celecoxib, an inhibitor of cyclooxygenase-2 (COX-2), is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. We determined whether continuous exposure to celecoxib would increase the antiproliferative effects of a 1-h treatment with docetaxel or cisplatin in four human ovarian cancer cell lines. COX-2 protein could not be detected in these cell lines, because of which three COX-2 positive human colon cancer cell lines were included. Multiple drug effect analysis demonstrated additive to borderline antagonistic effects of celecoxib combined with docetaxel. Combination indices with values of 1.4-2.5 in all cancer cell lines indicated antagonism between celecoxib and cisplatin regardless whether celecoxib preceded cisplatin for 3h, was added simultaneously or immediately after cisplatin. Apoptotic features measured in COX-2-negative H134 ovarian cancer cells and COX-2-positive WiDr colon cancer cells, such as the activation of caspase-3 and the number of cells in sub-G0 of the cell cycle, induced by docetaxel were increased in the presence of celecoxib, but were abrogated upon addition of celecoxib to cisplatin. Moreover, the G2/M accumulation in cisplatin-treated cells was less pronounced when celecoxib was present. Drugs did not affect p-Akt. Celecoxib upregulated p-ERK1/2 in H134 cells, but not in WiDr cells. Platinum-DNA adduct formation measured in WiDr cells, however, was reduced when celecoxib was combined with cisplatin. Taken together, our data demonstrate clear antagonistic effects when celecoxib is given concurrently with cisplatin, which is independent of COX-2 expression levels.
Bijman
Marcel N A
MN
Department of Medical Oncology, VU University medical center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Hermelink
Cristian A
CA
van Berkel
Maria P A
MP
Laan
Adrie C
AC
Janmaat
Maarten L
ML
Peters
Godefridus J
GJ
Boven
Epie
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000502:physiology*; D018736:DNA Adducts / Q000032:analysis; D000077143:Docetaxel; D004347:Drug Interactions; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018736:DNA Adducts; D011720:Pyrazoles; D013449:Sulfonamides; D043823:Taxoids; D000077143:Docetaxel; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D000068579:Celecoxib; D002945:Cisplatin