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    2020-07-08


    Conflicts of interest
    The authors declare no conflict of interest.
    References
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    2010. Anti-α-enolase autoantibodies are down-regulated in advanced cancer patients. Jpn. J. Clin. Oncol. 40, 663–669. Shridhar, R., Almhanna, K., Hoffe, S.E., Fulp, W., Weber, J., Chuong, M.D., Meredith, K.L., 2013. Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: a surveillance, epidemiology, and end results database analysis.
    Zavadil, J., Böttinger, E.P., 2005. TGF-beta and epithelial-to-mesenchymal transitions.
    Contents lists available at ScienceDirect
    Life Sciences
    journal homepage: www.elsevier.com/locate/lifescie
    Alpinumisoflavone causes DNA damage in Colorectal Cancer Cells via blocking DNA repair mediated by RAD51 
    T
    Dong Li , Xiaoyan Li, Genqu Li, Yan Meng, Yanghong Jin, Shuang Shang, Yanjie Li
    Department of Pharmacy, Puyang Oilfield General Hospital, Henan, China
    Keywords:
    Alpinumisoflavone
    CRC
    DNA-strand break
    Aims: Colorectal Cancer (CRC) accounts for 6.1% incidence and 9.2% mortality worldwide. The current study aimed to investigate the effect of alpinumisoflavone (AIF) on CRC and its possible molecular mechanism. Methods: HCT-116 and SW480 6-NBDG were chosen as cell model to study the anti-cancer activity of AIF in vitro experiments. Cells proliferative capacity and clonogenicity were examined by CCK-8 assay and colony formation assay, while cell apoptosis was detected by Hoechst 33258 staining and Flow cytometer. The protein expression levels of related gene were examined by western blotting. Transcriptome analyses were conducted to identify the differentially expressed genes in CRC cells, following AIF treatment. DNA damage was examined by γH2AX foci assay. The anti-cancer effect of AIF in vivo was validated in CRC xenograft model.
    Key findings: We found that AIF inhibited CRC cell proliferation and promoted apoptosis in a dose-dependent manner, as well as increased the number of γ-H2AX foci. In addition, microarray analysis showed that the DNA-double strand break (DSB) repair gene RAD51 was aberrantly overexpressed in CRC tissues, and was positively correlated with lymph node metastasis, TNM stage and poor outcomes. Both in vitro and in vivo experiments confirm that AIF treatment significantly decreased RAD51 levels. Knockdown RAD51 could enhance the anti-cancer activity of AIF against CRC, while abrogated by RAD51 overexpression.
    Significance: These findings suggest that AIF can be regarded as a potential anti-cancer drug and provide new insights into CRC treatment.
    1. Introduction
    Colorectal Cancer (CRC) is the fourth leading cause of cancer-re-lated deaths worldwide, and remains a serious public health problem [1]. The current treatment options of CRC, such as surgical resection, chemotherapy, and radiotherapy, offer limited survival benefits, and the 5-year mortality rate among the advanced CRC patients is still 50% [2]. Therefore, novel predictive and/or therapeutic biomarkers for CRC are urgently needed.
    DNA double-strand breaks (DSBs) are usually triggered by exo-genous chemical agents or ionizing radiation [3], and can lead to ge-netic instability and apoptosis. The lethal consequences of DSBs are alleviated or prevented by two main repair mechanisms: non-homo-logous end-joining (NHEJ) and homologous recombination (HR) [4]. RAD51, an important mediator of HR repair (HRR), is aberrantly overexpressed in various malignancies and is associated with radio- and chemo-resistance of the tumor cells, which often result in poor out-comes [5]. RAD51 promotes carcinogenesis and progression by inter-acting with p53, p21 and Bcl-2, and leads to mismatch repair and
    apoptosis evasion in the pre-malignant cells [5,6]. Following the DSB stimuli, the ataxia telangiectasia mutated (ATM) kinase phosphorylates the hydroxyl terminal of H2AX at the serine-139 residue, which sub-sequently recruits DNA-repair related proteins and cyclins to the da-maged site. Studies show that down-regulating H2AX levels in tumor cells enhances their sensitivity to chemo- and radiotherapy [7,8]. Taken together, targeting RAD51 and H2AX can potentially sensitize tumor cells to radio- and chemotherapy, and induce apoptosis.
    High-throughput screening of small-molecule libraries has helped discover numerous novel chemotherapeutic agents, including pacli-taxel, camptothecin, Vinca alkaloids and their derivatives etc. [9]. In recent decades, the focus of anti-cancer drug discovery has shifted to screening for the bioactive ingredients in natural products because of their lower toxicity and higher efficacy [10]. Alpinumisoflavone (AIF), the principal bioactive component isolated from D. eriocarpa, a tradi-tional Chinese medicine herb, has potent pharmacological properties, including atheroprotective [11], molluscicidal [12], estrogenic [13], and anti-bacterial activities [14]. Zhang et al. reported that AIF en-hanced the sensitivity of esophageal squamous cell carcinoma (ESCC)