Examination of Gossypol-Pluronic Micelles as Potential Radiosensitizers.

Abstract

Chemoradiotherapy, the combination of chemotherapy and radiotherapy to treat cancer, has the potential to enhance local therapeutic effects and simultaneously treat systemic disease. However, chemoradiotherapy may also enhance normal tissue effects leading to both acute and late toxicities. Furthermore, subtherapeutic chemoradiotherapy may result in aggressive tumor repopulation. Tumor-specific radiosensitizing chemotherapy may yield a synergistic therapeutic effect and avoid augmentation of normal tissue toxicity. In this study, the radiosensitizing effects of gossypol were investigated. Also, Pluronics were studied for gossypol solubilization and co-radiosensitization effects. Gossypol inhibits Bcl-2 and Bcl-XL, antiapoptotic proteins that are overexpressed in various cancer cells. Pluronic micelles (P85, F88, L35, and P123) effectively encapsulated gossypol, raising its water solubility by more than 1000-fold. Cytotoxic, anticlonogenic, and radiosensitizing effects were evaluated to characterize gossypol and Pluronic combinations. Gossypol and P85 had the strongest antiproliferative effect on A549 human lung adenocarcinoma cells in a cell viability assay. The IC50 value was seven times lower than gossypol only treatment (330 ± 70nM vs 2400 ± 400nM, (mean ± SE)). Gossypol and P85 showed significant inhibition of clonogenic survival, approximately 30% inhibition, compared to treatment with gossypol alone. An experimental sequencing study demonstrated greater inhibition of clonogenic survival when drug treatment followed radiation compared to a sequence of drug treatment followed by radiation. These results suggest that Pluronic micelles readily solubilize gossypol and that the combination of gossypol and P85 may augment the therapeutic effects of ionizing radiation.