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  • To the best of our knowledge there have

    2024-04-24

    To the best of our knowledge, there have been only a few reports on antiangiogenic activities about C. sanki, and its antiangiogenic constituents as well as its mechanism of action are worthy of further exploring and studying. Therefore, we carried out a bioassay-guided investigation of C. sanki in order to evaluate its antiangiogenic activities. Modern pharmacological researchshowedthatsome carbazole alkaloids possessed antiangiogenic activities [8], [9], [10]. In our previous work, the CHCl3 extract (active fraction) of C. sanki was revealed to display antiangiogenic activity, which prompted us to study its further active components. As a result, thirteen carbazole alkaloids 1–13 including two novel structures, named 6,7′-dimethoxy-3,3′,13,13′,14,14′-hexamethyl-9,9′-dihydro-[5,5′-bipyrano-carbazole]-6′,7-diol (1) and 1,9-dimethoxy-3-methyl-9H-carbazol-2-ol (2), were isolated and identified from C. sanki on the basis of extensive spectroscopic analysis and comparison with references (Fig. 1). Moreover, the known compounds 3–13 were isolated from C. sanki for the first time. Meanwhile, the isolates 1–13 of C. sanki were evaluated for their antiangiogenic activities in this work. These research results may guide the search for new natural products with antiangiogenic attributes.
    Materials and methods
    Results and discussion
    Conclusion In this work, thirteen carbazole alkaloids (1–13) were isolated and identified on the basis of spectroscopic analyses and references from C. sanki for the first time. Among then, compounds (1 and 2) were two new carbazole alkaloids, named 6,7′-dimethoxy-3,3′,13,13′,14,14′-hexamethyl-9,9′-dihydro-[5,5′-bipyrano-carbazole]-6′,7-diol (1) and 1,9-dimethoxy-3-methyl-9H-carbazol-2-ol (2), respectively. Meanwhile, compounds (1–13) were evaluated for their antiangiogenic activities by MTT assay to determine whether they decreased VEGF-mediated cell proliferation in human umbilical vascular endothelial AVE 0991 for the first time. The screening results of compounds (1–13) were shown in Table 2. Compounds 1, 2, 6, 8, and 13 (μM) exhibited certain antiangiogenic activities which inhibited VEGF-induced HUVEC proliferation in vitro. As a result, compounds 1, 2, 6, 8, and 13 (μM) exhibited moderate antiangiogenic activities with IC50 values of 12.1 (C.I. 8.2–15.2), 58.1 (C.I. 56.3–63.4), 13.7 (C.I. 9.2–15.4), 16.0 (C.I. 9.5–16.4), and 63.2 (C.I. 57.8–65.7) μM, respectively. In addition, compounds 1–13 were evaluated for antiangiogenic activities in the zebrafish embryo model in vivo, and compounds 1, 2, 6, 8, and 13 showed effectively suppress angiogenesis. These pharmacological screening results would guide the search for new natural products with antiangiogenic attributes.
    Acknowledgments This work was financially supported by the National Natural Science Foundation of China (NO. 11404373), the (NO. 172102310552), the Key Scientific Research Project of Colleges and Universities in Henan Province (NO. 17A350011), the Scientific and Technological Project of Nanyang (NO. KJGG23), the Laboratory Opening Program of Nanyang Normal University (NO. SYKF2016017), the Special Project of Nanyang Normal University (NO. ZX2014044).
    Introduction Drugs targeting tumor blood vessels are commonly used in cancer patients and they generally produce limited therapeutic benefits for survival improvement (Cao et al., 2011). One of the main hitches of low therapeutic efficacy is that cancer patients often develop resistance in response to antiangiogenic drug (AAD) treatment (Bergers and Hanahan, 2008, Cao and Langer, 2010, Cao et al., 2009, Casanovas et al., 2005, Chung et al., 2013, Crawford et al., 2009). Patients with cancers grown in organs adjacent to adipose tissues, including breast cancer, prostate cancer, pancreatic cancer, and hepatocellular carcinoma (HCC), show particularly low benefits from antiangiogenic therapy. These cancers located adjacent to adipose tissues often show intrinsic or acquired resistance to antiangiogenic therapy. For example, most patients with pancreatic ductal adenocarcinoma (PDAC) show intrinsic resistance and colorectal cancer (CRC) patients exhibit evasive resistance to bevacizumab (Van Cutsem et al., 2009). A puzzling observation in the field of antiangiogenic cancer therapy has been the inconsistency of drug effects in preclinical animal models and in cancer patients (Cao et al., 2011). While most AADs produce overwhelming anti-tumor effects in mouse models, the same drug often lacks anti-cancer effect in human patients. Among numerous possible reasons, the location of tumor implantation in animal models is often different from clinical situations. For example, subcutaneous implantation is a common location for studying animal tumors for the sake of convenience in monitoring tumor growth. However, human tumors rarely originate from a subcutaneous location.