Xanthohumol exhibits anti-myeloma activity in vitro through inhibition of cell proliferation, induction of apoptosis via the ERK and JNK-dependent mechanism, and suppression of sIL-6R and VEGF production

• Published in: Biochimica et biophysica acta. General subjects Vol. 1863; no. 11; p. 129408
• Main Authors: Sławińska-Brych, Adrianna, Zdzisińska, Barbara, Czerwonka, Arkadiusz, Mizerska-Kowalska, Magdalena, Dmoszyńska-Graniczka, Magdalena, Stepulak, Andrzej, Gagoś, Mariusz
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2019
• Subjects: acetylcysteine; antineoplastic activity; Apoptosis; Apoptosis - drug effects; caspase-3; cell cycle; Cell Line, Tumor; cell lines; cell proliferation; Cell Proliferation - drug effects; cyclins; cytotoxicity; enzyme inhibitors; enzyme-linked immunosorbent assay; Flavonoids - pharmacology; flow cytometry; fluorescence; Humans; immunoblotting; MAP Kinase Kinase 4 - metabolism; MAP Kinase Signaling System - drug effects; MAPKs; mitochondria; mitogen-activated protein kinase; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; myeloma; Neoplasm Proteins - metabolism; Propiophenones - pharmacology; protein synthesis; Receptors, Interleukin-6 - metabolism; ROS; signal transduction; sIL-6R; staining; therapeutics; Vascular Endothelial Growth Factor A - metabolism; vascular endothelial growth factors; VEGF; viability; Xanthohumol; Xanthohumol; VEGF; sIL-6R; Multiple myeloma; ROS; Apoptosis; MAPKs
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.08.001

Xanthohumol (XN, a hop-derived prenylflavonoid) was found to exert anticancer effects on various cancer types. However, the mechanisms by which XN affects the survival of multiple myeloma cells (MM) are little known. Therefore, our study was undertaken to address this issue. Anti-proliferative activity of XN towards two phenotypically distinct MM cell lines U266 and RPMI8226 was evaluated with the MTT and BrdU assays. Cytotoxicity was determined with the LDH method, whereas apoptosis was assessed by flow cytometry and fluorescence staining. The expression of cell cycle- and apoptosis-related proteins and the activation status of signaling pathways were estimated by immunoblotting and ELISA assays. XN reduced the viability of RPMI8226 cells more potently than in U266 cells. It blocked cell cycle progression through downregulation of cyclin D1 and increased p21 expression. The marked apoptosis induction in the XN-treated RPMI8226 cells was related to initiation of mitochondrial and extrinsic pathways, as indicated by the altered p53, Bax, and Bcl-2 protein expression, cleavage of procaspase 8 and 9, and elevated caspase-3 activity. The apoptotic process was probably mediated via ROS overproduction and MAPK (ERK and JNK) activation as N-acetylcysteine, or specific inhibitors of these kinases prevented the XN-induced caspase-3 activity and, hence, apoptosis. Moreover, XN decreased sIL-6R and VEGF production in the studied cells. ERK and JNK signaling pathways are involved in XN-induced cytotoxicity against MM cells. General Significance: The advanced understanding of the molecular mechanisms of XN action can be useful in developing therapeutic strategies to treat multiple myeloma. [Display omitted] •XN possessed in vitro the anticancer activity against multiple myeloma (MM) cells.•The anti-proliferative activity of XN was related to blockade of cell cycle progression at G1 phase.•XN was found to induce ROS generation•ERK and JNK signaling pathways seemed to be implicated in induction of apoptosis by XN.•XN was able to reduce the production of VEGF and sIL-6R in cultured MM cells.