Exp Mol Med.  2008 Dec;40(6):617-628. 10.3858/emm.2008.40.6.617.

Liposomal honokiol, a potent anti-angiogenesis agent, in combination with radiotherapy produces a synergistic antitumor efficacy without increasing toxicity

• Hu J
• Chen LJ
• Liu L
• Chen X
• Chen PL
• Yang G
• Hou WL
• Tang MH
• Zhang F
• Wang XH
• Zhao X
• Wei YQ

• KMID: 1072942
• DOI: http://doi.org/10.3858/emm.2008.40.6.617

Abstract

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.

Keyword

angiogenesis inhibitors; honokiol; liposomes; radiation tolerance; radiotherapy

MeSH Terms

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