Combination therapy between paclitaxel and γ-radiation results in cell cycle-dependent antagonistic interactions Free

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Combination therapy with anticancer drugs and radiation is common practice in the treatment of cancer. The interaction between drugs and radiation may create enhancement of tumor response such as synergistic or additive effect, but such a combination may also cause an antagonistic or resistive effect. In this study, we assessed the in vitro interactions between γ-radiation and paclitaxel, administrated at three different sequences designed as pre-radiated, co-radiated and post-radiated combinations in BCap37 (human breast cancer cell line) and KB (human epidermoid carcinoma cell line) cells. Through a series of experiments including MTT assay, DNA fragmentation, flow cytometric analysis and morphological examinations, we found that the combination between γ-radiation and paclitaxel did not show a synergistic or additive effect. Instead, we found that the in vitro cytotoxicity of paclitaxel was significantly decreased by γ-radiation, particularly when paclitaxel was combined with 10 Gy γ-radiation. Further analyses indicated that γ-radiation interfered with the capacity of paclitaxel to induce apoptosis as well as mitotic arrest. Finally, we demonstrated that γ-radiation resulted in a temporary (2 Gy) or prolonged (10 Gy) cell cycle arrest at G₂ phase, which obviously prevented the cytotoxic effect of paclitaxel on mitotic arrest and subsequently apoptosis. In addition, Western blots showed that γ-radiation was able to inhibit paclitaxel-induced IκBα degradation and bcl-2 phosphorylation, and increase the inhibitory phosphorylation of p34^cdc2, which provide further proof for the antagonistic and cell-cycle dependent interaction between the two modalities. Put together, these findings suggest that γ-radiation might specifically block the cell cycle at G₂ phase and, thereby, result in the cell cycle-dependent antagonistic effect on the antitumor activity of paclitaxel, which might be implicated in the clinical application of combination therapy between paclitaxel and radiation (Supported by NIH Grants CA92280 and CA82440).