Chemosensitization by fibroblast growth factor-2 is not dependent upon proliferation, S-phase accumulation, or p53 status

Abstract

Fibroblast growth factor-2 (bFGF/FGF-2) is a pleiotropic growth factor that functions as a survival factor and directs apoptosis during embryogenesis and development. As a survival factor, FGF-2 would be expected to protect cells against drug toxicities. Such protection has been reported in some cells treated with some chemotherapeutic drugs. However, we recently demonstrated that FGF-2 can sensitize NIH 3T3 mouse fibroblasts to the cytotoxic and apoptotic effects of cisplatin. Sensitization requires prolonged incubation of cells with FGF-2 before the addition of cisplatin, and it requires an FGF-2 concentration (5–10 ng/mL) that is higher than that needed for its mitogenic effects (0.5 ng/mL). We now report that FGF-2 can also sensitize MCF7 human breast cancer cells and A2780 human ovarian cancer cells, as well as NIH 3T3 cells, to cisplatin. FGF-2 did not affect the cisplatin sensitivity of SKOV3 ovarian cancer cells or a panel of seven pancreatic cancer cell lines. We have demonstrated that the sensitizing effect is not simply a function of the mitogenic activity of FGF-2 on cells, as we did not observe sensitization with other growth-stimulatory factors (FGF-1 and epidermal growth factor); the sensitizing effect of FGF-2 was observed even with cell lines that were not growth-stimulated by FGF-2; and sensitization was not restricted to cells in S-phase of the cell cycle. These results indicate that cell proliferation is neither necessary nor sufficient for sensitization by FGF-2. Moreover, sensitization to cisplatin appears to be p53-independent, as p53-null 3T3 10-1 cells were equally sensitized by FGF-2. Finally, FGF-2 also sensitized NIH 3T3 and MCF7 cells to carboplatin, and had smaller effects on the sensitivity of these cell lines to doxorubicin and docetaxel. FGF-2 had no effect on sensitivity to etoposide in any cell line tested. Therefore, sensitization by FGF-2 was most effective with the platinum compounds, suggesting that this activity may be specific to particular mechanisms of drug action.