Environ Toxicol. 2009 May 12; Ji L, Liu T, Wang ZPyrrolizidine alkaloids (PAs) are well-known natural hepatotoxins. In this study, we investigated the protection of epidermal growth factor (EGF) against the hepatotoxicity of clivorine, which is an otonecine-type PA from traditional Chinese medicine Ligularia hodgsonii Hook. Cell viability assay and cell morphology observation showed that EGF (1 ng/mL) reversed clivorine-induced cytotoxicity on human normal liver L-02 cells. EGF (1 ng/mL) also inhibited clivorine-induced DNA fragmentation and caspase-3 cleavage. Our previous study has showed that antiapoptotic Bcl-xL degradation and mitochondrial-mediated apoptosis was involved in clivorine-induced hepatotoxicity. In this study, we found that EGF (1 ng/mL) inhibited clivorine-induced antiapoptotic Bcl-xL protein decrease, caspase-9 activation, and release of cytosolic cytochrome C. We further investigated the effects of vascular epidermal growth factor, basic fibroblast growth factor, and insulin-like growth factor-1 on clivorine-induced cytotoxicity, and there is no significant protection observed. Our results suggest that EGF exerts its protective effects against clivorine-induced hepatotoxicity probably by modulating mitochondrial-mediated apoptotic signal pathway. (c) 2009 Wiley Periodicals, Inc. Environ Toxicol, 2009.

Food Chem Toxicol. 2009 May 4; Ma C, Yue QX, Guan SH, Wu WY, Yang M, Jiang BH, Liu X, Guo DACyclophosphamide (Cy) could induce immuno-suppression such as thymus atrophy and inhibition of lymphocyte proliferation response in mice. But;the mechanism of its effect is still not clear. Polysaccharides isolated from spore of Garnoderma lucidum (GL-SP) could;at least partly;restore the immunological effects against Cy-induced immuno-suppression. In the present study;a two-dimensional gel electrophoresis (2-DE)-based comparative proteomic method was conducted to identify the possible target-related proteins of Cy in mice thymus including those could be influenced by GL-SP. Fifteen proteins differentially expressed in Cy-treated mice compared with control were identified. Among the fifteen proteins;combined use of GL-SP with Cy could not affect Cy-induced expression change of three proteins;totally prevented Cy-induced expression change of six proteins;partly prevented Cy-induced expression change of four proteins and further enhanced Cy-induced expression change of two proteins. Results of the present study shed light on the mechanism of Cy-induced immuno-suppression as well as the protective effect of GL-SP against toxicity of Cy.

Mol Pharm. 2008 Nov-Dec; 5(6): 1044-54Gao Y, Chen L, Gu W, Xi Y, Lin L, Li YDocetaxel is one of the most promising chemotherapeutic agents for the treatment of metastatic breast cancer, but it shows fearful side effects. We hypothesized that a novel targeted nanoassembly (TNA) could provide efficient intracellular drug delivery in breast tumor cells overexpressing epidermal growth factor (EGF) receptor and thus improve the efficacy and reduce the side effects of docetaxel. We prepared the novel docetaxel loaded TNAs formed by polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) and modified with EGF. Compared with nontargeted nanoassemblies (NNAs), TNAs showed obvious improvement of cell-specific uptake and internalization, and revealed more cytotoxicity against MDA-MB-468 cells by inducing more late apoptosis and subG1 cells at low drug concentration, or more G2/M arrest at high drug concentration than NNAs or Taxotere. In BALB/c mice bearing breast tumor xenografts, TNAs showed stronger inhibition of tumor growth compared with NNAs (relative tumor volume in mice treated with 5 mg/kg TNAs = 0.99 and 10 mg/kg NNAs = 1.71, p < 0.05) or Taxotere (relative tumor volume in mice treated with 5 mg/kg TNAs = 0.99 and 10 mg/kg Taxotere = 4.20, p < 0.01). In particular, tumor disappeared completely in the TNA group at a dose of 10 mg/kg. The maximum tolerated dose (MTD) of TNAs was about four times higher than that of Taxotere. TNAs also demonstrated a much longer circulation time in vivo and more drug accumulation in tumor in a murine breast cancer model than Taxotere. TNA treatment also prolonged survival of mice. These results suggested that TNAs could have more potential as a delivery system for breast cancer chemotherapy.