Improved therapeutic effectiveness by combining liposomal honokiol with cisplatin in lung cancer model.

BACKGROUND: Honokiol is a major bioactive compound extracted from Magnolia. The present study was designed to determine whether liposomal honokiol has the antitumor activity against human lung cancer as well as potentiates the antitumor activity of cisplatin in A549 lung cancer xenograft model, if so, to examine the possible mechanism in the phenomenon. METHODS: human A549 lung cancer-bearing nude mice were treated with liposomal honokiol, liposomal honokiol plus DDP or with control groups. Apoptotic cells and vessels were evaluated by fluorescent in situ TUNEL assay and by immunohistochemistry with an antibody reactive to CD31 respectively. RESULTS: The present study showed that liposomal honokiol alone resulted in effective suppression of the tumor growth, and that the combined treatment with honokiol plus DDP had the enhanced inhibition of the tumor growth and resulted in a significant increase in life span. The more apparent apoptotic cells in the tumors treated with honokiol plus DDP was found in fluorescent in situ TUNEL assay, compared with the treatment with control groups. In addition, the combination of honokiol and DDP apparently reduced the number of vessels by immunolabeling of CD31 in the tissue sections, compared with control groups. CONCLUSION: In summary, our data suggest that honokiol alone had the antitumor activity against human lung cancer in A549 lung cancer xenograft model, and that the combination of honokiol with DDP can enhance the antitumor activity, and that the enhanced antitumor efficacy in vivo may in part result from the increased induction of the apoptosis and the enhanced inhibition of angiogenesis in the combined treatment. The present findings may be of importance to the further exploration of the potential application of the honokiol alone or the combined approach in the treatment of lung carcinoma.

Antitumour activity of cationic-liposome-conjugated adenovirus containing the CCL19 [chemokine (C-C motif) ligand 19] gene.

CCL19 [chemokine (C-C motif) ligand 19; also known as MIP-3beta (macrophage inflammatory protein-3beta) or ELC (Epstein-Barr-virus-induced molecule 1 ligand chemokine)], one of the immunostimulatory cytokines, chemoattracts both DCs (dendritic cells) and T-lymphocytes. Adenoviral vector is one of the most used gene delivery vectors for cancer therapy because of its high gene-transfection efficiency. However, its wider application is limited, owing to immune responses that reduce transgene expression and decrease the efficacy of repeated administration. We constructed the recombinant replication deficient adenoviral vectors containing the CCL19 gene (Ad-CCL19) and combined them with PEG-PE [poly(ethylene glycol)-phosphatidylethanolamine]-modified cationic liposomes (Ad-CCL19/PEG-PE) for immunotherapy against murine fibrosarcoma. Although there were hardly any therapeutic differences between Ad-CCL19- and Ad-CCL19/PEG-PE-treated mice that were observed at the second administration, the final results demonstrated that Ad-CCL19/PEG-PE-treated mice survived much longer. The antitumour efficacy may be related to the high level of CCL19 after the final administration and lasting expression of IFN-gamma (interferon-gamma) and IL-12 (interleukin-12) in the Ad-CCL19/PEG-PE-treated group, which were measured by reverse-transcription PCR and ELISA. The results demonstrated that PEG-PE-cationic-liposome-conjugated adenovirus could prolong the expression of the therapeutic gene in vivo and may enhance the antitumour efficacy.

Induction of apoptosis by phenylisocyanate derivative of quercetin: involvement of heat shock protein.

Quercetin, a widely distributed bioflavonoid, inhibits the growth of various tumor cells. The present study was designed to investigate whether a novel quercetin derivative [phenylisocyanate of quercetin (PHICNQ)] exerts antitumor activity against K562 and CT26 tumor cell lines by inducing apoptosis, and to examine the possible mechanism in the phenomenon. The cell proliferation assay of K562 and CT26 tumor cells was determined by the trypan blue dye exclusion test. Apoptosis of PHICNQ-treated cells was determined by morphological analysis, agarose gel DNA electrophoresis and quantitated by flow cytometry after staining with propidium iodide. Cell cycle was evaluated by flow cytometry. The expression of heat shock protein 70 was checked by Western blot analysis. Our results showed that PHICNQ inhibited the proliferation of K562 and CT26 cells in a dose-dependent and time-dependent manner. PHICNQ was 308- and 73-fold more active on CT26 and K562 cells than quercetin, respectively. In addition to this cytostatic effect, treatment of K562 and CT26 tumor cells with PHICNQ induced apoptosis. PHICNQ treatment downregulated the expression of heat shock protein 70 more dramatically than quercetin treatment. These results suggest that PHICNQ is a more powerful antiproliferative derivative than quercetin, with cytostatic and apoptotic effects on K562 and CT26 tumor cells. PHICNQ may trigger apoptosis in tumor cells through inhibition of heat shock protein 70 synthesis and expression.

[Nanoliposomal quercetin inhibits formation of malignant ascites of hepatocellular carcinoma].

BACKGROUND & OBJECTIVE: Quercetin is a potential chemotherapeutic drug with many biological activities. However, the insolubility of quercetin seriously limits its clinical use. This study was to investigate the biodistribution of quercetin encapsulated by pegylated nanoliposomes and its therapeutic efficacy on the formation of carcinomatous ascites of hepatocellular carcinoma in mice. METHODS: Nanoliposomal quercetin was prepared with conventional rotary evaporation method. BALB/c mice inoculated with hepatocellular carcinoma cells (H22) at the anterior right subaxilla for twelve days were given intravascular injection with nanoliposomal quercetin at 1.5 mg/body (based on quercetin) at different time points. Then the levels of quercetin in the plasma, tumor tissues and normal organs were tested by high pressure liquid chromatography (HPLC). Various dosages of nanoliposomal quercetin were peritoneally given to tumor-bearing mice to determine the optimal dose. The tumor-bearing mice were treated intraperitoneally with 100 mg/kg nanoliposomal quercetin once a day for 14 days. The formation of malignant ascites, increase of body weight, survival time and peritoneal capillary permeability were assessed. Apoptotic cells in ascites were detected by flow cytometry. RESULTS: Nanoliposomal quercetin was a spherical particle with 25% drug content (W/W) and 130+/-20 nm in diameter. Nanoliposomal quercetin effectively aggregated in tumor tissues and its half-life period was 4 h. Nanoliposome quercetin inhibited the formation of malignant ascites of hepatocellular carcinoma model in a dose-dependent manner. Moreover, 100 mg/kg nanoliposomal quercetin significantly enhanced the apoptosis of cancer cells in ascites, inhibited the increase of body weight, reduced peritoneal capillary permeability and prolonged the survival time of tumor-bearing mice compared with PBS control. CONCLUSION: Nanoliposomal quercetin can effectively accumulate in tumor tissues and inhibit the formation of malignant ascites, thus it might be used as a potential antitumor drug which deserves future study.

[Experimental study of anti-cancer effect of Mannan-modified targeted nanoliposome on mice].

OBJECTIVE: To test the anti-cancer effect of mannan-modified targeted nanoliposome on mice. METHODS: The 3beta[N-(N',N'-dimethylaminoethane) -carbamoyl] cholesterol (DC-chol) was synthesized by the chemical reaction of cholesteryl chloroformate and N, N-dimethylethylendiamine. The DC-chol was then mixed with dioleoylphosphatidylethanolamine (DOPE) and chol-AECM-mannan to produce the sonicated mannan-modified targeted nanoliposome. The size of the nanoliposome was measured by zetasizer. Nanoliposome or purified EGFR (as control) was injected to the C57 mice with implanted lung cancers intravenously. The growth of tumors was observed, followed by ELISA and Western tests of serum antibodies. RESULTS: The liposome nanoparticle had a size of 132 nm. The experimental groups had significant higher levels of blood serum antibodies than the controls. The experimental groups also had less volumes of tumors than the controls (P<0.05). CONCLUSION: The growth of tumor has been inhibited by mannan-modified targeted nanoliposome. The mannan-modified targeted nanoliposome has anti-cancer effect on mice.

Liposomal quercetin efficiently suppresses growth of solid tumors in murine models.

PURPOSE: Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro. EXPERIMENTAL DESIGN: Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues. RESULTS: Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis. CONCLUSIONS: Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.