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  • br Appendix A Supplementary data br

    2022-08-15


    Appendix A. Supplementary data
    References
    A. Bofin, G.M. Maelandsmo, L.A. Akslen, O. Engebraaten, I.S. Gribbestad, In vivo MRI and histopathological assessment of tumor microenvironment in luminal-like and basal-like breast cancer xenografts, J. Magn. Reson. Imaging 35 (5) (2012) 1098–1107.
    O. Engebraten, G.M. Maelandsmo, B. Johansen, S.A. Moestue, Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model, BMC Cancer 16 (2016) 191.
    Contents lists available at ScienceDirect
    Bioorganic & Medicinal Chemistry
    journal homepage: www.elsevier.com/locate/bmc
    Caged-xanthone from Cratoxylum formosum ssp. pruniflorum inhibits malignant cancer phenotypes in multidrug-resistant human A549 lung cancer AEB071 through down-regulation of NF-κB 
    T
    Chutima Kaewpiboona, , Nawong Boonnakb, Natpaphan Yawutc, Sirichat Kaowinnc, Young-Hwa Chungc, a Department of Biology, Faculty of Science, Thaksin University, Patthalung 93210, Thailand b Department of Basic Science and Mathematics, Faculty of Science, Thaksin University, Songkhla 90000, Thailand c Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 46241, Republic of Korea
    Keywords:
    MDR cancer
    Caged-xanthone
    Cochinchinone C
    Epithelial–mesenchymal transition
    Our recent study reported that multidrug-resistant (MDR) human A549 lung cancer cells (A549RT-eto) with the elevated expression of NF-κB showed epithelial–mesenchymal transition (EMT), increasing spheroid formation and elevating the expression levels of stemness-related factors, including Oct4, Nanog, Sox2, Bmi1, and Klf4. Therefore, when new therapeutic agents targeting these malignant cancer cells were explored, we found that caged-xanthone (CX) isolated from the roots of Cratoxylum formosum ssp. pruniflorum diminished the expression of NF-κB, P-glycoprotein (P-gp) protein levels, cell migration and invasion, and sphere-forming ability of A549RT-eto cells. To address the role of NF-κB in these malignant cancer features, we treated A549RT-eto cells with NF-κB siRNAs in the present work. We found that the knockdown of NF-κB inhibited EMT and sphere formation. Furthermore, co-treatment with CX and NF-κB siRNA accelerated the death of apoptotic cells through the decrease of P-gp protein levels. These results suggest that NF-κB was involved in malignant cancer pheno-types and MDR in A549RT-eto cells. Taken together, our findings suggest that CX can be a potential therapeutic agent for the treatment of malignant tumor cells.
    1. Introduction
    Nowadays, a major hurdle in cancer therapy is multidrug resistance (MDR) due to overexpression of a drug efflux protein, P-glycoprotein (P-gp). As a membrane transporter protein, P-gp is an energy-dependent drug efflux pump that maintains intracellular drug concentrations below cytotoxic levels, thereby decreasing the cytotoxic effects caused by a variety of chemotherapeutic agents.1–4 In particular, recent results have shown that a transcription factor NF-κB is activated in a range of human cancers and thought to promote MDR cancers mainly because of its ability to protect transformed cells from apoptosis.5 Moreover, NF-κB plays a key role in cancer development and metastasis. These multistep processes involve local tumor growth and invasion, followed by dis-semination to and re-establishment at distant sites.6 Metastasis occurs through a series of steps: local invasion, intravasation, transport, ex-travasation, and colonization. A developmental program termed as epithelial–mesenchymal transition (EMT) has been demonstrated to play a critical role in promoting the progression of malignant tumors.7
    In addition, cancer stem cells (CSCs) represent a small subset of cancer cells that are characterized by their self-renewal capability and plur-ipotent differentiation potential similar to those of normal stem/pro-genitor cells. Therefore, CSCs are believed to be of great significance in carcinogenesis, tumor growth, metastasis, and cancer recurrence.8 Moreover, CSCs are capable of forming suspended spherical, clonal colonies, also called sarcospheres, and they preferentially express key marker genes of pluripotent embryonic stem cells such as Oct-3/4 and Nanog.9 Thus, the elucidation of the molecular pathways for the de-velopment of malignant cancer phenotypes provides a clue for treat-ments from natural products.