title: Butein impairs the protumorigenic activity of malignant pleural mesothelioma cells.
abstract: Chronic inflammation appears to be a driving force behind cancer progression. NFκB and STAT3 activation plays a pertinent role in this process by mediating chemoresistance and the acquisition of mesenchymal features of protumorigenic cells. Epidemiological data and experimental observations suggest that Malignant Pleural Mesothelioma (MPM) is a prototype of chronic inflammation-driven cancer. Chemoresistance is a major feature of MPM. Thus, this paper explores the effect of butein (3,4,2',4'-tetrahydroxychalcone), a naturally occurring NFκB and STAT3 inhibitor, on the tumorigenic properties of MPM cells. MPM cells harbor high nuclear levels of NFκB and pSTAT3(Y(705)). Butein inhibits pSTAT3(Y(705)) phosphorylation, nuclear localization of NFκB and the physical interaction of NFκB and pSTAT3. This correlates with a downregulation of several genes involved in cancer progression (such as ICAM1, Vimentin, MMP9, Twist) of proangiogenic cytokines (VEGF) and of IL-6 and IL-8, key growth factors for MPM. Hence, butein inhibits the migration of MPM cells and strongly affects the clonogenicity of MPM cells in vitro. Finally, we show that the in vitro actions of butein translate into anticancer effects in vivo. In fact, butein treatment severely affects tumor engraftment and potentiates the anticancer effects of pemetrexed in mouse xenograft models. Butein does not significantly affect the viability of human, untransformed mesothelial cells in vitro, nor does it affect survival of tumor-free mice in vivo. The possibility of using butein as an additional treatment to current MPM therapies is discussed here.
authors.affiliation: Translational Oncogenomics Unit, Italian National Cancer Institute, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cioce
authors.forename: Claudia
authors.initials: C
authors.lastname: Canino
authors.forename: Claudio
authors.initials: C
authors.lastname: Pulito
authors.forename: Paola
authors.initials: P
authors.lastname: Muti
authors.forename: Sabrina
authors.initials: S
authors.lastname: Strano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D047188:Chalcones / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000068437:Pemetrexed; D010766:Phosphorylation; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047188:Chalcones; D005971:Glutamates; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D051879:Twist-Related Protein 1; D042461:Vascular Endothelial Growth Factor A; D014746:Vimentin; D000068437:Pemetrexed; D018799:Intercellular Adhesion Molecule-1; C040918:butein; D006147:Guanine; D020780:Matrix Metalloproteinase 9