Natural products are often used in drug development due to their ability to form unique and diverse chemical structures. Coumestans are polycyclic aromatic plant secondary metabolites containing a coumestan moiety, which consists of a benzoxole fused to a chromen-2-one to form 1-Benzoxolo[3,2-c]chromen-6-one. These natural compounds are known for large number of biological activities. Many of their biological effects can be attributed to their action as phytoestrogens and polyphenols. In the last decade, anticancer effects of these compounds have been described in vitro but there is only limited number of studies based on models in vivo. More information concerning their in vivo bioavailability, stability, metabolism, toxicity, estrogenicity, cellular targets and drug interactions is therefore needed to proceed further to clinical studies. This review focuses on coumestans exhibiting anticancer properties and summarizes mechanisms of their toxicity to cancer cells. Moreover, the possible role of coumestans in cancer prevention is discussed.
Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper-independent proteasome inhibitor. We conclude that the cytotoxicity of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells.
Dissemination of cancer cells to distant organs has fatal consequences to most of the patients with malignant tumors. Patients with prostate and breast cancer show apparent overlap of the most common sites of cancer metastasis, suggesting that breast and prostate tumor cells share common mechanisms of dissemination and colonization. During each step of prostate and breast cancer metastasis, malignant cells display phenotypic plasticity that is associated with the manifestation of epithelial and mesenchymal properties or an epithelial-to-mesenchymal transition (EMT). One of the molecules that most likely interlink processes of pathologic plasticity of cancer cells, their dissemination capability, and response to microenvironmental factors is Tumor-Associated Calcium Signal TransDucer 2 (Trop-2, TACSTD2). Trop-2 is a type-I transmembrane glycoprotein encoded by TACSTD2 gene often associated with tumorigenesis and cancer progression, but the data remain controversial. Trop-2 deregulation has been repeatedly proposed as an event associated with cancer progression and poor patient prognosis. Instead of this simplistic view, our results showed Trop-2 level change as a context-dependent, dynamic event associated with cancer plasticity and dissemination. Using antibody-based surface profiling of selected cancer stem-like cell markers in human and mouse prostate and breast cancer cell lines, we identified subpopulation of Trop-2+ cells within culture of metastatic prostate cell line DU-145 and similarly Trop-2+ subpopulation within mouse mammary cancer cell line 4T1. Gene expression analysis of sorted subpopulations showed significant correlation of Trop-2 with epithelial phenotype, and this finding was further validated in wide panel of human and murine cell lines and independent patient datasets. We further proved that expression of Trop-2 is regulated by EMT transcription factors and DNA methylation. Moreover, immunohistochemical analysis of Trop-2 in pairs of primary prostate tumors and lymph node metastasis showed strong association with E-cadherin and epithelial-mesenchymal plasticity in patient samples. In conclusion, we showed that Trop-2 expression associates with epithelial phenotype and can be suppressed either epigenetically or through the action of EMT master regulators. Acknowledgments: This work was supported by Ministry of Health of the Czech Republic, grant no. 15-33999A and 15-28628A, and by GAČR 15-11707S, HistoPARK (CZ.1.07/2.3.00/20.0185), and by project FNUSA-ICRC (no. CZ.1.05/1.1.00/02.0123) and ICRC-ERA-HumanBridge a.k.a. REGPOT (Grant agreement no. 316 345) from the European Regional Development Fund. Citation Format: Ján Remšík, Lucia Binó, Zuzana Kahounová, Gvantsa Kharaishvili, Sarka Simeckova, Radek Fedr, Tereza Nehybova, Eva Slabáková, Lucia Knopfová, Jan Bouchal, Milan Kral, Petr Benes, Karel Soucek. Trop-2 plasticity is driven by epithelial-to-mesenchymal transition in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B084.
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