kurarinone and Breast-Neoplasms

We have analyzed in molecular detail how kurarinone, a lavandulyl flavanone isolated from Sophora flavescens, suppresses nuclear factor-κB (NFκB)-driven interleukin-6 (IL6) expression and cancer cell growth. Interleukin-6 (IL6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes responsivity to hormones and to chemotherapeutics. Our results in estrogen-unresponsive fibroblasts, ribosomal S6 kinase 2 kinase (RSK2) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that kurarinone can inhibit tumor cell proliferation and selectively block nuclear NFκB transactivation of specific target genes such as IL6, cyclin D1, SOD2 but not TNFAIP2. This occurs via attenuation of extracellular signal-regulated protein (ERK) and RSK2 kinase pathways and inhibition of S6 kinase ribosomal protein (S6RP) and histone H3 S10 phosphorylation. As constitutive NFκB and RSK2 activity are important hallmarks of human cancers, including hematopoietic malignancies and solid tumors, prenylated flavanones represent an attractive class of natural inhibitors of the ERK/RSK2 signaling pathway for cancer therapy.

Topics: Animals; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Flavanones; Flavonoids; Gene Expression Regulation, Enzymologic; Humans; MAP Kinase Signaling System; Mice; NF-kappaB-Inducing Kinase; Plant Extracts; Plant Roots; Protein Serine-Threonine Kinases; Ribosomal Protein S6 Kinases, 90-kDa; Sophora

Kurarinone, a lavandulyl flavanone, was isolated from a polyphenolic extract of the roots of Sophora flavescens using fractionation guided by estrogenic activity, which was determined by recombinant yeast and Ishikawa Var-I bioassays. Kurarinone showed weak estrogenic activity both in the yeast screen and in the Ishikawa Var-I assay with EC(50) values of 4.6 and 1.66 microM, respectively. Furthermore, kurarinone was found to have potent cytotoxic activity (IC(50) value = 22.2 microM) against human MCF-7/6 breast cancer cells in the sulforhodamine-B assay.

Topics: Antineoplastic Agents, Phytogenic; Belgium; Breast Neoplasms; Drug Screening Assays, Antitumor; Estrogens; Female; Flavonoids; Humans; Inhibitory Concentration 50; Molecular Structure; Phytotherapy; Plants, Medicinal; Sophora; Tumor Cells, Cultured