Synergistic antitumor effects of liposomal honokiol combined with adriamycin in breast cancer models

Abstract

Honokiol, a novel antitumor agent, could induce apoptosis and inhibit the growth of vascular endothelium in several tumor cell lines and xenograft models. It has been suggested that the antitumor effect of chemotherapy could be increased by combining it with an antiangiogenesis agent in anticancer strategy. The present study explored the potential to increase the antitumor effect of adriamycin by combining it with honokiol in mouse 4T1 breast cancer models, and the underlining mechanism was investigated. Honokiol was encapsulated in liposomes to improve the water insolubility. In vitro, liposomal honokiol inhibited the proliferation of 4T1 cells via apoptosis and significantly enhanced the apoptosis of 4T1 cells induced by adriamycin. In vivo, the systemic administration of liposomal honokiol and adriamycin significantly decreased tumor growth through increased tumor cell apoptosis compared with either treatment alone. Collectively, these findings suggest that liposomal honokiol may augment the induction of apoptosis in 4T1 cells in vitro and in vivo, and this combined treatment has shown synergistic suppression in tumor progression according to the analysis of isobologram. The present study may be important in future exploration of the potential application of the combined approach in the treatment of breast cancer.

Self-Assembled Hydrophobic Honokiol Loaded MPEG-PCL Diblock Copolymer Micelles

“…Previous reports demonstrated that honokiol could treat cancers by causing cell cycle arrest (6,7), inhibiting angiogenesis (8), and inducing apoptosis (9)(10)(11)(12). Meanwhile, honokiol could overcome conventional drug resistance (13)(14)(15) and also showed synergistic antitumor effect with other anticancer agents such as cisplatin or adriamycin (16,17). When many studies around the pharmacodynamics and pharmacology of honokiol attract great attention, questions around the formulation of honokiol should also be attended due to the fact that honokiol is water insoluble.…”

“…The honokiol loaded MPEG-PCL micelle (ca.21 nm) was stable, easy to produce and scale up, and had high drug loading (20%). Previously, many protocols have been performed in our laboratory to make honokiol injectable, including liposomal honokiol (15)(16)(17), honokiol loaded F127 micelle (29), honokiol loaded PCL-PEG-PCL nanoparticles (30,31), and honokiol loaded self-assembled PCL-PEG-PCL micelles (32). This work was precisely designed on the basis of our previous studies.…”

Liposomal honokiol inhibits VEGF‐D‐induced lymphangiogenesis and metastasis in xenograft tumor model

“…The liposomal honokiol was prepared in our laboratory 17 and described briefly as follows: PC, cholesterol, PEG4000 and honokiol in weight ratios of 1:0.15:0.24:0.22 were dissolved in 15 mL chloroform/methanol at a ratio of 3:1 (v/v) and evaporated under vacuum in a rotary evaporator until a thin lipid film was formed. The dried lipid films were left overnight and sonicated in 5% glucose solution followed by concentrated and lyophilized.…”

“…15 Our previous studies have shown that honokiol possesses significant antitumor effect as well as an enhancement in tumor growth delay and improvement of survival by combination with cisplatin in ovarian carcinoma 16 or with adriamycin in breast cancer models. 17 The poor water solubility of honokiol could be improved by encapsulating honokiol with PEG modified liposome. 17 However, it is still unclear whether honokiol effectively inhibits lymphangiogenesis and its related lymphatic metastasis.…”

“…17 The poor water solubility of honokiol could be improved by encapsulating honokiol with PEG modified liposome. 17 However, it is still unclear whether honokiol effectively inhibits lymphangiogenesis and its related lymphatic metastasis.…”