Radiosensitivity of human colon cancer cell enhanced by immunoliposomal docetaxel

AIM: To enhance the radiosensitivity of human colon cancer cells by docetaxel.METHODS: Immunoliposomal docetaxel was prepared by coupling monodonal antibody against carcinoembryonic antigen to cyanuric chloride at the PEG terminus of liposome. LoVo adenocarcinoma cell line was treated with immunoliposomal docetaxel or/and irradiation. MTT colorimetric assay was used to estimate cytotoxicity of immunoliposomal docetaxel and radiotoxicity. Cell cycle redistribution and apoptosis were determined with flow cytometry. Survivin expression in LoVo cells was verified by immunohistochemistry. D801 morphologic analysis system was used to semi-quantify immunohistochemical staining of survivin.RESULTS: Cytotoxicity was induced by immunoliposomal docetaxel alone in a dose-dependent manner. Immunoliposomal docetaxel yielded a cytotoxicity effect at a low dose of 2 nmol/L. With a single dose irradiation, the relative surviving fraction of LoVo cells showed a dosedependent response, but there were no significant changes as radiation delivered from 4 to 8 Gy. Compared with liposomal docetaxel or single dose irradiation,strongly radiopotentiating effects of immunoliposomal docetaxel on LoVo cells were observed. A low dose of immunoliposomal docetaxel could yield sufficient radiosensitivity. Immunoliposomal docetaxel were achieved both specificity of the conjugated antibody and drug radiosensitization. Combined with radiation,immunoliposomal docetaxel significantly increased the percentage of G2/M cells and induced apoptosis, but significantly decreased the percentage of cells in G2/G1 and S phase by comparison with liposomal docetaxel.Immunohistochemical analysis showed that the brown stained survivin was mainly in cytoplasm of LoVo cells.Semi-quantitative analysis of the survivin immunostaining showed that the expression of survivin in LoVo cells under irradiation with immunoliposomal docetaxel was significantly decreased.CONCLUSION: Immunoliposomal docetaxel is strongly effective for target radiosensitation in LoVo colon carcinoma cells, and may offer the potential to improve local radiotherapy.

The Grape Component Resveratrol Interferes with the Function of Chemoattractant Receptors on Phagocytic Leukocytes

Resveratrol (3, 5, 4'-trihydroxystilbene) (RV) is a constituent of grape seeds with anti-inflammatory andanti-oxidant activities. In this study, we examined the capacity of RV to modulate the function of Gprotein-coupled chemoattractant receptors, which play important roles in inflammation and immune responses.RV, over a non-cytotoxic concentration range, inhibited chemotactic and calcium mobilization responses ofphagocytic cells to selected chemoattractants. At low micromolar concentrations,RV potently reducedsuperoxide anion production by phagocytic leukocytes in response to the bacterial chemotactic peptide fMLF, ahigh affinity ligand for formylpeptide receptor FPR, and Ap.4z, an Alzheimer's disease-associated peptide and aligand for the FPR variant FPRL1. In addition, RV reduced phosphorylation of extracellular signal-regulatedkinase (ERK1/2) and the activation of nuclear factor NF-KB induced by formylpeptide receptor agonists. Theseresults suggest that the inhibition of the function of chemoattractant receptors may contribute to theanti-inflammatory properties of RV Thus, RV may be therapeutically promising for diseases in which activationof formylpeptide receptors contributes to the pathogenic processes. Cellular&Molecular Immunology. 2004;1(1):50-56.

Chemokines and Chemokine Receptors as Novel Therapeutic Targets in Rheumatoid Arthritis (RA):Inhibitory Effects of Traditional Chinese Medicinal Components

Chemokines belong to a large family of inflammatory cytokines responsible for migration and accumulation of leukocytes at inflammatory sites.Over the past decade,accumulating evidence indicated a crucial role for chemokines and chemokine receptors in the pathophysiology of rheumatoid arthritis(RA).RA is a chronic autoimmune disease in which the synovial tissue is heavily infiltrated by leukocytes.Chemokines play an important role in the infiltration,localization,retention of infiltrating leukocytes and generation of ectopic germinal centers in the inflamed synovium.Recent evidence also suggests that identification of inhibitors directly targeting chemokines or their receptors may provide a novel therapeutic strategy in RA.Traditional Chinese medicines(TCMs) have a long history in the treatment of inflammatory joint disease.The basis for the clinical benefits of TCM remains largely unclear.Our studies have led to the identification of numerous novel chemokine/chemokine receptor inhibitors present in anti-inflammatory TCMs.All of these inhibitors were previously reported by other researchers to have anti-arthritic effect,which may be attributable,at least in part,to their inhibitory effect on chemokine and/or chemokine receptor.Therefore,identification of agents capable of targeting chemokine/chemokine receptor interactions has suggested a mechanism of action for several TCM components and provided a means of identifying additional anti-RA TCM.Thus,this approach may lead to the discovery of new inhibitors of chemokines or chemokine receptors that can be used to treat diseases associated with inappropriately overactive chemokine mediated inflammatory reactions.Cellular & Molecular Immunology.2004;1(5):336-342.

Transcriptional Crosstalk between Nuclear Receptors and Cytokine Signal Transduction Pathways in Immunity

The nuclear receptor superfamily and the transcriptional factors associated with cytokines are inherently different families of signaling molecules and activate gene transcription by binding to their respective responsive element.However,it has become increasingly clear from our works and others that nuclear receptors are important regulators of cytokine production and function through complex and varied interactions between these distinct transcriptional factors.This review provides a general overview of the mechanism of action of nuclear receptors and their transcriptional crosstalk with transcriptional factors associated with cytokine transduction pathways.One of the most important mechanistic aspects is protein to protein interaction through a direct or co-regulator-mediated indirect manner.Such crosstalk is crucially involved in physiological and therapeutic roles of nuclear receptors and their iigands in immunity, inflammation and cytokine-related tumors.Cellular & Molecular Immunology.2004;1(6):416-424.