In vitro susceptibility to anticancer agents of the human KB carcinoma cell line transfected with COX-2 cDNA.
In order to investigate the malignant phenotype of cyclooxygenase (COX)-2 overexpressing cancer cells, a human epidermoid KB carcinoma cell line minimally expressing COX-2 protein was transfected with human COX-2 cDNA. In this study, we used a COX-2 transfected clone KB/COX-2 and a neomycin-transfected clone KB/neo as the control. When we examined the susceptibility to anticancer agents, there was no difference between these two clones in vincristine, bleomycin and 5-fluorouracil, although KB/COX-2 showed a 2.5-fold resistance to cisplatin (CDDP) as compared with KB/neo. The IC50 for CDDP was 4.3 microM in KB/COX-2 and 1.7 microM in KB/neo. Treatment with small interfering RNA (siRNA) mediated the inhibition of COX-2 significantly increasing the level of susceptibility to CDDP in COX-2 siRNA as compared to that of the control siRNA. The expression of MRP1 and MRP2 was stronger in KB/COX-2 than in KB/neo by Western blot analysis. In addition, apoptosis induction by CDDP was at a lower level in KB/COX-2 (31%) than in KB/neo (38%). These results suggested that the overexpression of COX-2 increases the intracellular production of MRP1 and MRP2 and causes drug resistance to CDDP.
Takaoka
Kazuki
K
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo, Japan. ktaka@hyo-med.ac.jp
Kishimoto
Hiromitsu
H
Segawa
Emi
E
Otsu
Nao
N
Zushi
Yusuke
Y
Hashitani
Susumu
S
Noguchi
Kazuma
K
Urade
Masahiro
M
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007624:KB Cells; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D014750:Vincristine / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001761:Bleomycin; D002945:Cisplatin; D051546:Cyclooxygenase 2; D018076:DNA, Complementary; D005472:Fluorouracil; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D034741:RNA, Small Interfering; D014750:Vincristine; C000715087:ABCC2 protein, human; C496540:PTGS2 protein, human; C421109:multidrug resistance-associated protein 1