Tamoxifen modulation of carboplatin cytotoxicity in a human U-138 glioma cell line

Glioma cells express high protein kinase C (PKC) activity, which may represent an important therapeutic target. Tamoxifen (TAM) has moderate PKC-inhibiting activity, blocking DNA synthesis and cellular proliferation in human glioma cells at concentrations that can be achieved therapeutically. Carboplatin (CBDCA), a second-generation platinum derivative, induces intra- and interstrand DNA-protein crosslinks producing inhibition of tumor-cell growth. In the present study, the effect of TAM, CBDCA, and the combination of both was evaluated against the human established U-138 glioma cell line during the exponential growth phase (48–72 h) by means of both the Biorad protein assay (BPA) method and Trypan blue exclusion study (TBES). Both TAM and CBDCA reduced the cellular growth rate, with a median 50%-inhibiting concentration (IC50) of 12.5 μM for TAM and 350 μM for CBDCA. The U-138 glioma cell line showed a moderate response to 100 μM of CBDCA, with ≤10% reduction of the growth rate. The association of both chemotherapeutic agents induced a 98% reduction of the IC50 dose of TAM (0.1 μM), and a 71% reduction of the IC50 dose of CBDCA (100 μM). During the combinational TAM–CBDCA exposure we observed a cytotoxic effect of TAM at concentrations lower than 0.1 μM, not recognized using it as a single drug. The differences observed among the IC50 doses (TAM, CBDCA, TAM–CBDCA) and among treated and untreated matched control cells were statistically significant (P<0.01). Our results confirm previous observations about the efficacy in vitro of TAM against human glioma cell lines and show a marked enhancement of this activity by CBDCA.