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    Conflicts of interest
    The authors report no conflict of interest in this study.
    This research was supported by the Ministry of Science and Technology of the People's Republic of China (No. 2018ZX09201018-
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    Anti-lung cancer activity and inhibitory mechanisms of a novel Calothrixin T A derivative
    Xiaohong Yang, Jiangsheng Gao, Jian Guo, Zimeng Zhao, Shao-Lin Zhang , Yun He
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, 55 South Daxuecheng Road, Chongqing 401331, PR China
    Topo I inhibitor
    Cell ABT-263 arrest
    Aims: CAA45 is a calothrixin A (CAA) analogue with anti-cancer activity at nanomolar concentration. This study aimed to investigate the anti-lung cancer activity of CAA45 and explore its mechanisms of actions.
    Main methods: CAA and CAA45 were synthesized and their inhibition on DNA topoisomerase I (Topo I) per-formed by evaluating the relaxation of supercoiled pBR322 plasmid DNA and their anti-lung cancer capacity determined by cytotoxic assays, cell migration, cell cycle, cell apoptosis, cell autophagy and related signaling proteins expression by western blot.
    Key findings: CAA45 significantly inhibited human non-small cancer cell A549 and NCI-H1650 cells growth with IC50 values of 110 and 230 nM, respectively. In the A549 xenograft models, CAA45 displayed strong antitumor activities at a dose of 10 mg/kg. CAA45 inhibited Topo I activity and caused the cell cycle arrest at S phase, which also reduced A549 cell migration by inhibiting MMP-2 and MMP-9 expressions. Furthermore, CAA45 induced A549 cell apoptosis and autophagy. The apoptosis pathway was involved in the release of cytochrome c and caspase activation. CAA45 also inhibited Akt, activated JNK and up-regulated p53 signals in A549 cells, which may serve as a modulator to induce apoptosis and autophagy in cancer cells.
    Significance: CAA45 exerted its anti-lung cancer effect via inhibition of Topo I, resulting in cell cycle arrest and cell migration, induction of mitochondria mediated cell apoptosis and autophagy via PI3K/Akt/JNK/p53 pathway. All these observations suggested that CAA45 could be a promising lead for anti-cancer drug discovery.
    1. Introduction
    Lung cancer is one of the leading causes of cancer-related mortality in China. The reported data showed that approximately 733,300 people were diagnosed with lung cancer and 610,200 died in China in 2015 [1]. The predominant form of this disease is non-small-cell lung cancer (NSCLC), with majority of patients diagnosed at advanced stages [2]. For many decades, cytotoxic drugs such as docetaxel, paclitaxel, pla-tinum, gemcitabine and gefitinib were used for the treatment of NSCLC patients in clinic [3,4]. However, with the long-term use of the cyto-toxic drugs, there is an increase in drug-resistance and genetic altera-tions of cancer cells over the last decade, which limit their usage [4]. To overcome these defects, researchers have been searching for novel scaffolds that function by binding to novel sites on clinically well va-lidated targets which are conserved among cancer cells.
    DNA topoisomerase I (Top I) is a well-known anticancer target, which is essential for topological manipulation of DNA during cellular events such as replication, transcription and repair. Calothrixin A (CAA)