Honokiol is an active compound purified from magnolia that has been shown to induce cell differentiation, apoptosis, and anti-angiogenesis effects, as well as an enhancement in tumor growth delay in combination with chemotherapeutic agents in several mouse xenograft models. Our goal was to investigate the radiosensitization effect of honokiol on lung carcinoma. The radiosensitization effect of liposomal honokiol in Lewis lung carcinoma cells (LL/2) was analyzed using an in vitro clonogenic survival assay. For an in vivo study, Lewis lung carcinoma-bearing C57BL/6 mice were treated with either liposomal honokiol at 25 mg/kg or 5 Gy of single tumor radiation, or a combination of both over 12 days of treatment. The tumor growth delay and the survival time were evaluated. In addition, histological analysis of tumor sections was performed to examine changes by detecting the microvessel density and apoptosis in tumor tissues. In the clonogenic survival assay, LL/2 cells treated with IC50 Lipo-HNK for 24 h showed a radiation enhancement ratio of 1.9. After 12 days of combination treatment, the tumor volume decreased 78% and produced an anti-tumor activity 1.3-fold greater than a predicted additive effect of honokiol and radiation alone. This combination treatment also caused an 8.7 day delay in tumor growth. The cell cycle distribution and histological analysis demonstrated that liposomal honokiol has an anti-tumor effect via inducing apoptosis and inhibiting angiogenesis. Liposomal honokiol can enhance tumor cell radiosensitivity in vitro and in vivo, indicating that radiotherapy combined with liposomal honokiol can lead to greater anti-tumor efficacy.
Angiogenesis Inhibitors/administration & dosage/*therapeutic use ; Animals ; Apoptosis ; Biphenyl Compounds/administration & dosage/*therapeutic use ; Carcinoma, Lewis Lung/drug therapy/radiotherapy/*therapy ; Cell Cycle/drug effects/radiation effects ; Cell Line, Tumor ; Combined Modality Therapy ; Humans ; Lignans/administration & dosage/*therapeutic use ; Liposomes ; Lung Neoplasms/drug therapy/radiotherapy/*therapy ; Magnolia/chemistry ; Mice ; Neoplasm Transplantation ; Neovascularization, Pathologic/drug therapy/radiotherapy ; Radiation Tolerance ; Transplantation, Heterologous

Hypoxia is a common phenomenon in solid tumors. Resistance of hypoxic tumor cells to radiation is a significant reason of failure in the local control of tumors. The growth and metastasis of solid tumors rely on blood vessels. Antiangiogenic agents mainly target tumor blood vessels, and radiation therapy mainly targets tumor cells. Combination of antiangiogenic treatment and radiation exhibits synergistic effect, which improves the response of tumors to radiation therapy. The mechanisms of interaction between antiangiogenic agents and ionizing radiation are complex and involve interactions between tumor cells and tumor microenvironment, including tumor oxygenation, stroma, and vasculature. The original mechanism of antiangiogenesis is to induce ischemia and hypoxia in tumors, thereby, "starve" the tumors. However, recently, emerging data suggest that antiangiogenic agents could reduce the proportion of hypoxic cells through normalizing tumor vasculature, decreasing oxygen consumption, and other mechanisms. The use of antiangiogenic agents provides a new approach to overcome the hypoxia problem, and ultimately improves the efficacy of radiation therapy. In this review, we discuss tumor hypoxia, tumor angiogenesis and its regulation, mechanisms of antiangiogenic therapy combined with radiation therapy, and how antiangiogenic therapy overcomes tumor hypoxia.
Angiogenesis Inhibitors ; pharmacology ; therapeutic use ; Animals ; Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Antibodies, Monoclonal, Humanized ; pharmacology ; therapeutic use ; Apoptosis ; drug effects ; Bevacizumab ; Cell Hypoxia ; drug effects ; Combined Modality Therapy ; Endostatins ; pharmacology ; therapeutic use ; Humans ; Neoplasms ; blood supply ; drug therapy ; metabolism ; radiotherapy ; Neovascularization, Pathologic ; drug therapy ; Oxygen Consumption ; drug effects ; radiation effects