Enhancement of therapeutic effectiveness by combining liposomal honokiol with cisplatin in ovarian carcinoma

Abstract

Honokiol, a well-tolerated natural product, can inhibit the proliferation of cancer cells. But its water insolubility hampers its systemic administration for therapy of cancer. As a drug delivery system, the pegylated liposome (PEGL) can increase the water solubility and targeting of the drug. Honokiol has been successfully encapsulated by PEGL in our laboratory. We wondered whether the combination treatment with pegylated liposomal honokiol (H-PEGL) and cisplatin (DDP) could improve the antitumor efficacy in ovarian carcinoma. H-PEGL could introduce apoptosis of SKOV3 cells in vitro, which was quantified by flow cytometric analysis, and the cellular morphologic changes were determined by propidium iodide staining. In a human ovarian carcinoma mouse model, combination treatment with H-PEGL (0.4 mg/day for 30 days; intraperitoneal) and DDP (5 mg/kg on days 7, 11, 15, 19; intraperitoneal) acted synergistically to inhibit tumor growth by 91.48% without notable toxicity, but H-PEGL and DDP alone only inhibit tumor growth by 66.83% and 52.5% as compared to the NaCl solution control, respectively. Assessment of microvessel density and apoptosis index by CD31 and terminal deoxynucleotidyl transferase-mediated nick end labeling immunohistochemistry respectively suggested that the antitumor activity of H-PEGL is mediated by angiogenesis inhibition and introduction of apoptosis. Our results showed us a splendid prospect of the clinical application of combination treatment on patients suffering from ovarian cancer with H-PEGL and DDP.

Induction of Apoptosis and Inhibition of Angiogenesis by PEGylated Liposomal Quercetin in Both Cisplatin-Sensitive and Cisplatin-Resistant Ovarian Cancers

“…25 Images of cells were taken using ZEISS AXIOVERT 200 microscope and Axio Cam MRm camera. Besides, the apoptosis of the cells was quantified by flow cytometric analysis as described elsewhere.…”

c-Myc is a novel target of cell cycle arrest by honokiol in prostate cancer cells

“…12,15,19,20 Furthermore, liposomal HNK was shown to sensitize cancer cells to drugs such as cisplatin. 21 In summary, preclinical evidence for anticancer effect of HNK is quite persuasive.…”

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

“…16,[34][35][36] As a carrier for antitumor drugs, liposome has been shown to reduce side effects by accumulating preferentially at tumor sites. Our current studies indicate that honokiol-encapsulated liposome have shown improvement of water solubility.…”

“…12,13 The underlying molecular mechanisms may contribute to the inhibition of phosphorylation of AKT, p42/ 44 MAPK. 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.…”