Browsing by Author "Dong, Zi-Zheng"

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    Drugging the “Undruggable” DNA-binding Domain of STAT3 for Inhibition of Cancer Cell Migration and Invasion
    (Office of the Vice Chancellor for Research, 2013-04-05) Huang, Wei; Liu, Jing-Yuan; Dong, Zi-Zheng; Wang, Fang; He, Yan-Tao; Hangoc, Giao; Fu, Xin-Yuan; Broxmeyer, Hal; Zhang, Zhong-Yin; Zhang, Jian-Ting
    Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors, and its activation is associated with high histological grade and advanced cancer stage. STAT3 has been shown to play important roles in multiple aspects of cancer aggressiveness including migration, invasion, survival, self-renewal, angiogenesis, and tumor cell immune evasion by regulating the expression of multiple downstream target genes. Thus, inhibiting STAT3 promises an attracting strategy for treatment of advanced tumors with metastatic potential. Previously, we identified a STAT3 inhibitor, inS3-54, by targeting the “undruggable” DNA-binding site of STAT3 using an improved in-silico screening approach. To further develop this inhibitor, we identified 79 analogues of inS3-54 for the structure-activity relationship analysis. Further study of five effective analogues shows that four analogues (#1, 18, 26, and 69) inhibit STAT3-dependent colony formation of hematopoietic progenitor cells, indicating a higher selectivity for STAT3 than their parental compound, inS3-54 and another analogue #74. These compounds also (1) inhibit STAT3-specific DNA binding activity; (2) suppress proliferation of cancer cells that have constitutively activated STAT3; and (3) inhibit migration and invasion of cancer cells. In addition, analogue #26-conjugated Sepharose beads could also pull down STAT3, revealing a possible direct binding between STAT3 and the inhibitor. Taken together, we conclude that it is possible to inhibit STAT3 by targeting its DNA-binding domain for discovery of anticancer therapeutics and for treatment of metastatic cancers.
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    Effect of eIF3a on response of lung cancer patients to platinum-based chemotherapy by regulating DNA repair
    (American Association for Cancer Research, 2011) Yin, Ji-Ye; Shen, Jie; Dong, Zi-Zheng; Huang, Qiong; Zhong, Mei-Zuo; Feng, De-Yun; Zhou, Hong-Hao; Zhang, Jian-Ting; Liu, Zhao-Qian; Pharmacology and Toxicology, School of Medicine
    Purpose: The purpose of this study is to test the hypothesis that eIF3a may regulate the expression of DNA repair proteins which, in turn, affects response of lung cancer patients to treatments by DNA-damaging anticancer drugs. Experimental design: Immunohistochemistry was used to determine the expression of eIF3a in 211 human lung cancer tissues followed by association analysis of eIF3a expression with patient's response to platinum-based chemotherapy. Ectopic overexpression and RNA interference knockdown of eIF3a were carried out in NIH3T3 and H1299 cell lines, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin, doxorubicine, etoposide (VP-16), vincristine, and vinblastine by using MTT assay. The DNA repair capacity of these cells was evaluated by using host-cell reactivation assay. Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of eIF3a on the DNA repair genes by using cells with altered eIF3a expression. Results: eIF3a expression associates with response of lung cancer patients to platinum-based chemotherapy. eIF3a knockdown or overexpression, respectively, increased and decreased the cellular resistance to cisplatin and anthrocycline anticancer drugs, DNA repair activity, and expression of DNA repair proteins. Conclusions: eIF3a plays an important role in regulating the expression of DNA repair proteins which, in turn, contributes to cellular response to DNA-damaging anticancer drugs and patients' response to platinum-based chemotherapy.