title: The COX-2 inhibitor Celecoxib enhances the sensitivity of KB/VCR oral cancer cell lines to Vincristine by down-regulating P-glycoprotein expression and function.
abstract: Previous studies have indicated that long-term chemotherapy decreases the sensitivity of oral cancer cells to chemotherapeutics while simultaneously increasing resistance to these drugs. COX-2 inhibitors are known to enhance the toxic action of anti-tumor drugs against cancer cells. Using the MTT method, we investigated the influence of the COX-2 selective inhibitor Celecoxib on the proliferation of KB/VCR oral cancer cell lines and analyzed the effect of Celecoxib on the regulation of P-glycoprotein (P-gp) expression and function. Western blot analysis was employed to detect the expression of P-gp, and flow cytometry was used to evaluate P-gp function by detecting the accumulation of the active P-gp functional fluorescence substrate within KB/VCR cells. The results revealed that a low dose of Celecoxib (10 μmol/L) showed no growth inhibitory effects on KB/VCR cell lines. When the concentration of Celecoxib was greater than or equal to 20 μmol/L, the inhibitory effect on KB/VCR cells was significantly enhanced in a time- and dose-dependent manner. The lower dose of Celecoxib (10 μmol/L) significantly enhanced the toxicity of Vincristine (VCR) against KB/VCR cell lines. After the application of Celecoxib plus VCR (10 μmol/L+1.5μmol/L, respectively) treatment for 24, 48 or 72 h, the growth inhibition rates of KB/KBV cells were 37.82 ± 1.60%, 47.84 ± 1.29% and 54.43 ± 2.35%, respectively, which were significantly higher than the rates in the cells treated only with Celecoxib (10 μmol/L) or VCR (1.5 μmol/L) (all P<0.01). P-gp expression levels in KB/KBV cells treated with Celecoxib plus VCR (10 μmol/L+1.5 μmol/L, respectively) were markedly lower than the levels in control cells and those treated with VCR (1.5 μmol/L) (all P<0.01). In addition, the intensity of Rho123 fluorescence of KB/KBV cells in cells treated with Celecoxib plus VCR (10 μmol/L+1.5 μmol/L, respectively) or Celecoxib alone (10 μmol/L) was significantly higher than the intensity observed in control cells and those treated with VCR alone (1.5 μmol/L) (all P<0.01). The underlying mechanism of these phenomena is likely correlated with the down-regulation of the expression and function of P-gp due to Celecoxib, thereby increasing the amount of VCR accumulated in KB/VCR cells.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Road, Guangzhou 510515, China. yanyixuan001@163.com
authors.forename: Yi Xuan
authors.initials: YX
authors.lastname: Yan
authors.forename: Wei Zhong
authors.initials: WZ
authors.lastname: Li
authors.forename: Yan Qing
authors.initials: YQ
authors.lastname: Huang
authors.forename: Wen Xiao
authors.initials: WX
authors.lastname: Liao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007624:KB Cells; D009062:Mouth Neoplasms / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D014750:Vincristine; D051546:Cyclooxygenase 2; D000068579:Celecoxib