Quan-cheng Chen

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Organization: Xiamen University

Department: School of Pharmaceutical Sciences

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Chemicals
References

Honokiol sensitizes breast cancer cells to TNF- induction of apoptosis by inhibiting Nur77 expression

Co-reporter:Lei Xie;Fuquan Jiang;Xindao Zhang;Gulimiran Alitongbieke;Xinlei Shi;MinJun Meng;Yiming Xu;Anshi Ren;Jing Wang;Lijun Cai;Yunxia Zhou;Yang Xu;Ying Su;Jie Liu;Zhiping Zeng;Guanghui Wang;Hu Zhou;Quan Cheng Chen;Xiao-kun Zhang

British Journal of Pharmacology 2016 Volume 173( Issue 2) pp:344-356

Publication Date(Web):

DOI:10.1111/bph.13375

Background and Purpose

The orphan nuclear receptor Nur77 is implicated in the survival and apoptosis of cancer cells. The purpose of this study was to determine whether and how Nur77 serves to mediate the effect of the inflammatory cytokine TNF-α in cancer cells and to identify and characterize new agents targeting Nur77 for cancer therapy.

Experimental Approach

The effects of TNF-α on the expression and function of Nur77 were studied using in vitro and in vivo models. Nur77 expression was evaluated in tumour tissues from breast cancer patients. The anticancer effects of honokiol and its mechanism of action were assessed by in vitro, cell-based and animal studies.

Key Results

TNF-α rapidly and potently induced the expression of Nur77 in breast cancer cells through activation of IκB kinase and JNK. Knocking down Nur77 resulted in TNF-α-dependent apoptosis, while ectopic Nur77 expression in MCF-7 cells promoted their growth in animals. Levels of Nur77 were higher in tumour tissues than the corresponding tissues surrounding the tumour in about 50% breast cancer patients studied. Our in vitro and animal studies also identified honokiol as an effective sensitizer of TNF-α-induced apoptosis by inhibiting TNF-α-induced Nur77 mRNA expression, which could be attributed to its interference of TNFR1's interaction with receptor-interacting protein 1 (RIPK1).

Conclusions and Implications

TNF-α-induced Nur77 serves as a survival factor to attenuate the death effect of TNF-α in cancer cells. With its proven human safety profile, honokiol represents a promising agent that warrants further clinical development.

Structural modification of ginsenoside Rh2 by fatty acid esterification and its detoxification property in antitumor

Co-reporter:Gong-Qing Wei, Yi-Nan Zheng, Wei Li, Wen-Cong Liu, Ting Lin, Wei-Yun Zhang, Hai-Feng Chen, Jin-Zhang Zeng, Xiao-Kun Zhang, Quan-Cheng Chen

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 2) pp:1082-1085

Publication Date(Web):15 January 2012

DOI:10.1016/j.bmcl.2011.11.104

Ginsenoside Rh2, one of the most important ginsenosides with anticancer properties in red ginseng, has been developed as principal antitumor ingredient for clinical use. However, the cytotoxicity test in human hepatocyte cell line QSG-7701 (IC50 37.3 μM) indicated that Rh2 might show strong cytotoxic side-effect on the normal liver cells. For blunting the toxicity, Rh2 was structurally modified by reacting with octanoyl chloride to give a dioctanoyl ester of Rh2 (D-Rh2) in the present study. MTT assay in QSG-7701 cell line in vitro showed that the cytotoxicity of D-Rh2 on human hepatocyte cells (IC50 80.5 μM) was significantly lower than that of Rh2. While antitumor xenograft assay in mice bearing H22 liver cancer cells in vivo showed that the antitumor activity of D-Rh2 retained to be strong as that of Rh2. According to previous pharmacokinetic studies, the fatty acid esterification of Rh2 might be of detoxification reaction to cells. Additionally, D-Rh2 showed significant enhancement on increasing thymus index at the dose of 10 mg/kg compared with vehicle treated control group. Thus, D-Rh2 might indirectly affect tumor growth by stimulating lymphocytes to become cytotoxic to tumor cells. Finally, our findings suggested that D-Rh2, the fatty acid ester of Rh2, might attenuate the side-effect by detoxification to human normal cell and could be a more potential candidate for developing as an antitumor drug.