Ruizan Shi

Shanxi Medical University, Yangkü, Shanxi Sheng, China

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Publications (5)15.64 Total impact

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    ABSTRACT: Multidrug resistance (MDR) is a major obstacle that hinders the efficacy of chemotherapy in many human malignancies. PHⅡ-7 is a derivative of indirubin, which is designed and synthesized by our laboratory. Our preliminary work indicates its potent antitumor activities in vitro and in vivo. Furthermore, based on the model of MDR cell line, we found its powerful effect in inhibiting the expression of P-glycoprotein (P-gp) and killing multidrug-resistant (MDR) cells. However, the detailed mechanism of PHⅡ-7 remains to be explored. Reactive Oxygen Species are known for high reactive activity as they possess unmatched electrons. In this study, we showed that PHⅡ-7 generated equal reactive oxygen species in parental K562 and its counterpart MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine(NAC) almost abolished the cytotoxicity of PHⅡ-7. Moreover, NAC abrogated DNA damage, cell cycle arrests and apoptosis induced by PHⅡ-7. Our results collectively indicated that reactive oxygen species production induced by PHⅡ-7 contributed to both apoptosis and cell cycle arrets in MDR K562/A02 cells, thus extending our prior related findings. Notably, JNK phosphorylation was induced by PHⅡ-7 and pre-incubated of K562/A02 cells with NAC or inhibitor of JNK(SP006125) eliminated P-gp downregulation. Taken together, our results provide a detailed biochemical basis for further clinical application of PHⅡ-7.
    European journal of pharmacology 07/2013; · 2.59 Impact Factor
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    ABSTRACT: Chemotherapeutic drugs can enhance an immune response of the host against the tumor in addition to killing cancer cells by direct cytotoxicity. So the combination of chemotherapy and immunotherapy is a promising approach for eliminating tumors, particularly in advanced stages. A strategic medication is to use a bispecific antibody format which is capable of recruiting polyclonal T cells around antibody-target-expressing tumor cells. Recently, we have constructed a bispecific antibody, antiCD3-antiCD19, in a diabody configuration. In this study, we measured B7 family members B7.1 (CD80) and B7.2 (CD86) expressed on a CD19+ human leukemia cell line, Nalm-6, stimulated by cytosine arabinoside (Ara-C). We found that a low concentration of Ara-C could up-regulate CD80 expressed on CD19+ Nalm-6 cells. The cytotoxicity of T lymphocytes against Nalm-6 cells in vitro and in vivo mediated by antiCD3×antiCD19 diabody with or without low dose of Ara-C was compared. The combination of antiCD3×antiCD19 diabody and Ara-C showed the greatest effectiveness in enhancing the cytotoxicity of T cells against the tumor cells in vitro and in vivo. Activated T cells expressed higher levels of CD25 and CD69 and released more interleukin 2 (IL-2). Both perforin/granzyme B system and Fas/FasL pathway were involved in the diabody-induced T-cell cytotoxicity. Moreover, the activated T cells could up-regulate ICAM-3 expression on Nalm-6 cells, and inhibition of LFA-1-ICAM-3 interaction impaired cytotoxicity of T cells. It was noted that Ara-C could up-regulate CD80 expressed on 2 of 5 specimens of acute B lymphoblastic leukemia (B-ALL) patient-derived cells. Cytotoxicity of T cells against these two patient-derived cells was enhanced in the presence of antiCD3×antiCD19 diabody. These findings indicate that treatment strategy using both cytotoxic lymphocyte-based immunotherapy and chemotherapy may have synergistic effects.
    Human gene therapy 07/2013; · 4.20 Impact Factor
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    ABSTRACT: Multidrug resistance (MDR) is a major hurdle in the treatment of cancer. Research indicated that the main mechanisms of most cancers included so-called "pump" (P-glycoprotein, P-gp) and "non-pump" (apoptosis) resistance. Identification of novel signaling molecules associated with both P-gp and apoptosis will facilitate the development of more effective strategies to overcome MDR in tumor cells. Since the proto-oncogene c-fos has been implicated in cell adaptation to environmental changes, we analyzed its role in mediating "pump" and "non-pump" resistance in MCF-7/ADR, an adriamycin (ADR)-selected human breast cancer cell line with the MDR phenotype. Elevated expression of c-fos in MCF-7/ADR cells and induction of c-fos by ADR in the parental drug-sensitive MCF-7 cells suggested a link between c-fos and MDR phenotype. Down-regulation of c-fos expression via shRNA resulted in sensitization of MCF-7/ADR cells to chemotherapeutic agents, including both P-gp and non-P-gp substrates. Further results proved that c-fos down-regulation in MCF-7/ADR cells resulted in decreased P-gp expression and activity, enhanced apoptosis, and altered expression of apoptosis-associated proteins (i.e., Bax, Bcl-2, p53 and PUMA). All above facts indicate that c-fos is involved in both P-gp- and anti-apoptosis-mediated MDR of MCF-7/ADR cells. Based on these results, we propose that c-fos may represent a potential molecular target for resistant cancer therapy, and suppressing c-fos gene expression may therefore be an effective means to temper breast cancer cell's MDR to cytotoxic chemotherapy. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 03/2013; · 3.06 Impact Factor
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    ABSTRACT: Multidrug resistance (MDR) is a major impediment to the effective chemotherapy of many human malignancies, and novel MDR reversal agents are desirable for combination therapy to reduce MDR, enhance anti-tumor activity and reduce side effects. Overexpression of P-glycoprotein (P-gp) is the most prevalent cause of MDR in cancer tissues, and resistance to apoptosis is a common characteristic for the multidrug resistant cancer cells. Our group has synthesized a novel potent anti-tumor indirubin derivative, PHII-7. In this study, MCF-7/ADR cells, an adriamycin (ADR)-selected human breast tumor cell line with the MDR phenotype, were used to investigate the anticancer properties of this novel indirubin derivative. Cytotoxicity and apoptosis assays showed that PHII-7 significantly inhibited cell growth, induced apoptosis, potentiated ADR cytotoxicity and restored chemotherapy sensitivity in the MDR cancer cells. Further studies indicated that by down-regulation of P-gp expression, PHII-7 partially inhibited P-gp efflux pump function and increased intracellular accumulation of Rhodamine 123, a P-gp substrate. These results provide a biochemical basis for possible clinical application of PHII-7 alone or in combination with conventional antineoplastic agents in the treatment MDR tumors.
    European journal of pharmacology 08/2011; 669(1-3):38-44. · 2.59 Impact Factor
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    ABSTRACT: Here we constructed and produced a recombinant human 4-1BB ligand (4-1BBL)/anti-CD20 fusion protein and examined its antitumor activity, alone and in combination with an anti-CD3/anti-CD20 bispecific diabody. The 4-1BBL/anti-CD20 fusion protein retained both the costimulatory activity of 4-1BBL on T cells and the tumor targeting ability of CD20 antibody on B cells. The fusion protein bound as efficiently to 4-1BB- and CD20-positive cells as its respective parental antibodies, and was capable of cross-linking human T lymphocytes and CD20-positive tumor cells. Combination treatment with 4-1BBL/anti-CD20 fusion protein and anti-CD3/anti-CD20 diabody led to significantly increased T-cell cytotoxicity to human B-lymphoma cells in vitro and drastically more potent tumor inhibitory activity in vivo in xenografted B-cell lymphoma in severe combined immunodeficiency disease mice. Mechanistic studies revealed that the combination treatment remarkably inhibited apoptosis of human peripheral blood lymphocytes, accompanied by upregulation of Bcl-XL and Bf1-1, perforin and granzyme B mRNA, and increased interleukin-2 production. Taken together, these results suggest that targeted delivery of 4-1BBL to the tumor site, when combined with anti-CD3/anti-CD20 diabody, could strongly potentiate the antitumor activity of the diabody, thus may have significant clinical application in the treatment of human CD20-positive B-cell malignancies.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 06/2010; 33(5):500-9. · 3.20 Impact Factor