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  • br Disclaimer Statement br Acknowledgments

    2023-09-27


    Disclaimer Statement
    Acknowledgments
    Introduction Metabolic changes are a common feature of cancerous tissues. Mutations in oncogenes and tumor suppressor genes cause alterations to multiple intracellular signaling pathways that rewire tumor cell metabolism and re-engineer it to allow enhanced survival and growth. The extensive metabolic rewiring of malignant cells offers a large number of potential drug targets [1]. A proper intervention in a cancer metabolic pathway might provide a therapeutic advantage that can help overcome resistance to chemotherapy or radiotherapy [2]. The best characterized metabolic phenotype observed in tumor cells is the Warburg effect, which is a shift of ATP generation from oxidative phosphorylation to glycolysis, even under normal oxygen concentrations [3]. This effect is regulated by PI3K, hypoxia-inducible factor (HIF), p53, MYC and AMP-activated protein kinase (AMPK)–liver kinase B1 (LKB1) pathways. Another metabolic pathway often increased in cancer cells is lipid synthesis. Adenosine triphosphate (ATP) citrate lyase (ACL) is the cytosolic enzyme that catalyzes the synthesis of acetyl-CoA from citrate. Cytosolic acetyl-CoA is the requisite building block for endogenous synthesis of fatty acids, cholesterol and isoprenoids, as well as for posttranslational modification of proteins via acetylation. ACL is upstream of the other lipogenic enzymes and connects glucose metabolism (a way of generating acetyl CoA) and lipogenesis [4]. ACL also affects mitochondrial homeostasis and membrane potential through the increased availability of mitochondrial citrate for full oxidation and NADH production in the TCA cycle [5]. In tumor cells, de novo fatty NVP DPP 728 dihydrochloride synthesis occurs at high rates [6], [7], [8]. ACL was identified as a highly expressed protein in many tumors, including the chemoresistant colorectal cancer cells via unbiased proteomic profiling [9]. In agreement with reported results [4], [10], our own data demonstrated that ACL knockdown (KD) by shRNA limits tumor cell proliferation and survival, induces differentiation in vitro and in vivo, and reduces tumor growth in a number of animal models [11]. We have recently shown that ACL KD also targets cancer stem-like cells (CSCs) in multiple cancer types, suggesting that ACL inhibitors might be effective in reducing cancer stemness [12]. The presence of CSCs is believed to be a major underlying reason for the emergence of resistance to standard therapy and the occurrence of metastasis, major causes of treatment failure and mortality. Collectively, available data strongly support the notion that targeting ACL by small molecule inhibitors is an attractive strategy for developing an innovative cancer therapy to address the highly unmet needs in metastasis and drug resistance of cancers [13], [14], [15], [16]. Nature is a rich source for biologically active compounds, including the widely used anticancer therapeutics paclitaxel and doxorubicin. The natural product 2-chloro-1,3,8-trihydroxy-6-methyl-10H-anthracen-9-one (2a), which is structurally related to emodin (1a) isolated from the Chinese herbal plant Rheum palmatum L. [17], was reported to display inhibitory activity against the ACL enzyme [18]. Herein we describe the structure-activity relationship (SAR) study of emodin anthraquinones and anthracenone, the characterization of potent ACL inhibitors, and their in vitro anticancer activities. Further, we show for the first time that small molecule ACL inhibitors reduce cancer stemness in breast and lung cancer 3D spheroid assays.
    Results and discussion
    Conclusions In summary, we identified a new series of ACL inhibitors based on the chemical scaffold of the natural product emodin. SAR and docking analyses indicate that the two OH groups adjacent to the 9-carbonyl group may be critical for on-target activity. In addition, the auto docking studies NVP DPP 728 dihydrochloride indicated the formation of key interactions with N346 and G664 in an allosteric site adjacent to the citrate binding domain. Chemical modifications of the 2–5 positions of emodin lead to ACL inhibitors with IC50 ranging from 30 to 3 μM. Halogens at the 2- and 4-position of emodin increased activity most significantly, while aryl substituents at the 2-position of emodin resulted in moderately active ACL inhibitors. Lead compounds dose-dependently inhibited the proliferation of the A549 lung cancer cells, with the best compounds reaching to similar levels of activity to that of ACL KD. Further, we demonstrated for the first time that ACL inhibitors significantly reduced cancer stemness in the 3D spheroid assay. Our data provide further support to the approach of targeting ACL for treating cancers and will guide the future lead optimization studies.