Liposomal Honokiol Efficiently Inhibit Growth Of Ovarian Tumor In Mice

Objective:Ovarian cancer is a relatively common disease in developed countries and causes more death than any other cancer of the female reproductive system. and females. The therapeutic improvement on traditional surgery and radiotherapy seems to have reached a plateau. Efforts are continuing to develop new and less toxic chemotherapeutic agents for the treatment of ovarian cancer.Honokiol, a well-tolerated natural product, has many biological activities, such as antitumor, anti-proliferatic effects on a wide range of human cancer cell lines and inhibitions of glycolysis, macromolecule synthesis and enzymes. However, the extreme water insolubility hampers it's delivering to the tumor at an effective concentration. hampered by its extreme water insolubility. Liposomes have previously been used as carriers for delivery of a variety of drugs, including antibiotic, antifungal, chemotherapeutic drug, and biological agents. As carriers anticancer drugs, they have been shown to reduce side effects, improve water soubility, biodistribution, and metabilition of those drugs. In the present work, we encapsulated honokiol in the non- aqueous interior of the polyethylene glycol liposome. The anticancer efficacy of liposomal honokiol was observed in vivo and in vitro.Methods:The honokiol encapsulated by pegylated liposomes was preparated by film ultrasonic dispersion methods in our labortary. The tumor cells of human ovarian cacinoma lines (SKOV3 ) were treated with various dose liposomal honokiol or empty liposomes. Induction of apoptosis and effects on growth inhibition by liposomal honokiol were tested in vitro. To choose the optimal dose, SKOV3- bearing BABL/c nude mice were treated with liposomal honokiol at various doses. The abdominal cavity tumor of nude mice was established SKOV3 cells. The mice were randomly subdivided into four groups (n=5 each group) and treated with liposomal honokiol, empty liposomes, DDP or NS, respectively. Tumor volume and survival were observed. The mice beared subcutaneous SKOV3 cancer were also treated with liposomal honokiol, DDP, liposomal honokiol + DDP, NS, empty liposome (n=5 each group), reapectively. Tumor volume and tumor weight were observed. Antiangiogenesis of liposomal honokiol in vivo was determined by CD31 immunohistochemistry. Histologic analysis and assessment of apoptotic cells were also conducted in tumor tissues.Results:The honokiol encapsulated by pegylated liposomes could be dissolved in water soulation and keep stable in 4℃refrigratory for 1 month.The liposomal honokiol has a size of 130±20 nm, capsulated ratio is 85% . The liposomal honokiol induces apoptosis and significantly inhibited tumor cells growth in vitro in a dose- and time- dependent manner. The antitumor efficiency of liposomal honokiol was a dose-dependent way and the optimal dose of liposomal honokiol was 20mg/kg every day in the present studies. Liposomal honokiol clearly inhibited the growth of tumor and prolonged the survival of abdominal cavity tumor bearing mice compared with NS control or empty liposome (P<0.05). The combination of liposomal honokiol and cisplatin produced no obvious side effects, and significantly decreased subcutaneous SKOV3 tumor growth through decreasing tumor microvessel density(MVD) and increasing tumor cell apoptosis compared with each of every single treatment alone.Conclusion:The honokiol encapsulated by pegylated liposomes could dissolved in water soulation. The liposomal honokiol could effectively inhibit the proliferation of tumor cells in vitro and induce tumor cell apoptosis in a time- and dose- dependent ways. In vivo, the liposomal honokiol could obivously inhibit the growth of tumor-bearing mice in a dose-dependent way. The liposomal honokiol significantly inhibited angiogenesis as assessed by CD31 immunohistochemical and increase the rate of apoptosis and necrosis in the tumor tissues compared with controls.Our data suggest that liposomal honokiol can be a potential application in the treatment of ovarian carcinoma and the combination of liposomal honokiol with cisplatin can enhance the anti-tumor activity in ovarian carcinoma. These findings may be of importance for further exploration of the potential application of liposomal honokiol in the treatment of ovarian carcinoma.