Bufadienolides bufalin and cinobufagin are cardiotonic steroids isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor. They have been shown to induce a wide spectrum of cancer cell apoptosis. However, the detailed molecular mechanisms of inducing apoptosis in hepatocellular carcinoma (HCC) are still unclear. In the present study, the apoptosis-inducing effect of bufalin and cinobufagin on HCC cell line HepG 2 was investigated. We found bufalin and cinobufagin induced marked changes in apoptotic morphology and significantly increased the proportion of apoptotic cells. This apoptotic induction was associated with an increase in Fas, Bax and Bid expression, a decrease in Bcl-2 expression, disruption of the mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, -8, -9 and -10, and the cleavage of poly(ADP-ribose)polymerase (PARP), which indicated that bufalin and cinobufagin induced apoptosis through both Fas-and mitochondria-mediated pathways. In addition, caspase activation during bufalin-and cinobufagin-induced apoptosis was further confirmed by caspase-3 inhibitor Z-DEVD-FMK, caspase-8 inhibitor Z-IETD-FMK, caspase-9 inhibitor Z-LEHD-FMK and caspase-10 inhibitor Z-AEVD-FMK. The results showed that bufalin-and cinobufagin-induced apoptosis was blocked by these inhibitors and particularly by caspase-10 inhibitor. Taken together, bufalin and cinobufagin induce apoptosis of HepG 2 cells via both Fas-and mitochondria-mediated pathways, and a Fasmediated caspase-10-dependent pathway might play a crucial role. (Cancer Sci 2011; 102: 951-958) H epatocellular carcinoma (HCC) is one of the most common malignancies worldwide with 600 000 deaths per year, and its incidence is still on the rise.(1) Surgical treatments, such as liver resection and transplantation, are the first-line therapeutic strategies for HCC. However, the postoperative survival rate is only 30-40% at 5 years and recurrence is quite common in patients who have had a resection.(2) In addition, because HCC is a relatively chemo-resistant tumor and highly refractory to cytotoxic chemotherapy, systemic cytotoxic chemotherapy agents are minimally effective at improving the survival of patients with advanced HCC.(3,4) Therefore, development of novel chemotherapeutic agents and more effective therapies for the treatment of HCC are urgently needed. Recently, traditional Chinese medicines and their active components have attracted a great deal of attention as candidates for HCC therapy.(5)

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Human serum albumin (HSA) is used as an important plasma volume expander in clinical practice. However, the infused HSA may extravasate into the interstitial space and induce peripheral edema in treating the critical illness related to marked increase in capillary permeability. Such poor intravascular retention also demands a frequent administration of HSA. We hypothesize that increasing the molecular weight of HSA by PEGylation may be a potential approach to decrease capillary permeability of HSA. In the present study, HSA was PEGylated in a site-specific manner and the PEGylated HSA carrying one chain of polyethylene glycol (PEG) (20 kDa) per HSA molecule was obtained. The purity, PEGylated site and secondary structure of the modified protein were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), thiol group blockage method and circular dichroism (CD) measurement, respectively. In addition, the pharmacokinetics in normal mice was investigated, vascular permeability of the PEGylated HSA was evaluated in lipopolysaccharide (LPS)-induced lung injury mouse model and the pharmacodynamics was investigated in LPS-induced sepsis model with systemic capillary leakage. The results showed that the biological half-life of the modified HSA was approximately 2.3 times of that of the native HSA, PEG-HSA had a lower vascular permeability and better recovery in blood pressure and haemodilution was observed in rats treated with PEG-HSA. From the results it can be inferred that the chemically well-defined and molecularly homogeneous PEGylated HSA is superior to HSA in treating capillary permeability increase related illness because of its longer biological half-life and lower vascular permeability.

Zinc-doped copper oxide nanocomposites (nZn-CuO NPs) are novel nanparticles synthesized by our group. In the present study, the antitumor effects and the underlying molecular mechanisms of the nZn-CuO NPs were investigated. The cytotoxicity of nZn-CuO NPs against several types of cancer cell lines was studied using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)/phenazinemethosulfate (PMS) assay. Results showed that nZn-CuO NPs exerted obvious antiproliferation effects on cancer cells and relatively weak antiproliferation effects on normal cells. The antitumor mechanisms of nZn-CuO NPs were further investigated using human liver cancer HepG2 cells and human pancreatic cancer Panc28 cells. Hoechst 33342 staining and FITC-Annexin V/PI staining showed that nZn-CuO NPs could induce cell apoptosis in a dose dependent manner. Cell-cycle analysis using flow cytometry revealed that nZn-CuO NPs were able to arrest the cell cycle in the G2/M phase. Also, nZn-CuO NPs were found to induce reactive oxygen species (ROS) generation. Further studies confirmed that nZn-CuO NPs could increase p-IKKα/β and nucleus p-NF-κB p65 expressions and decrease IKKα, IKKβ, IκBα, and nucleus NF-κB p65 expressions in both cell lines. Overall, our data demonstrated that nZn-CuO NPs could selectively inhibit the growth of cancer cells via ROS-mediated NF-κB activation. The current study provides primary evidence that nZn-CuO NPs possess the potential to be developed as a novel anticancer agent.

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