title: Alantolactone induces G1 phase arrest and apoptosis of multiple myeloma cells and overcomes bortezomib resistance.
abstract: Several sesquiterpene lactones have been extracted and demonstrated to exert various pharmacological functions in a variety of cancers. Here, we investigated anti-tumor effect of alantolactone, an allergenic sesquiterpene lactone, on human multiple myeloma (MM) and showed alantolactone inhibited growth of MM cells, both in the presence or absence of bone marrow (BM)-derived stromal cells (HS-5), and subsequent G1 phase arrest, and apoptosis as demonstrated by increased Annexin-V/7-AAD binding, caspase-3 or caspase-9 activation and down-modulation of activation of extracellular signal-regulated kinases 1/2. In addition, alantolactone reduced the secretion of MM survival and growth-related cytokines, vascular endothelial growth factor, from MM cells or HS-5 cells, and inhibited cytokine-induced osteoclastogenesis. Notably, alantolactone also inhibited cell proliferation in bortezomib-resistant MM cells. Taken together, alantolactone exerted anti-tumor effect on MM by suppressing cell proliferation, triggering apoptosis, partly damaging the BM microenvironment and overcoming proteasome inhibitor resistance, suggesting alantolactone may be a novel therapeutic approach for the treatment of human MM.
authors.affiliation: Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, 99, West Huaihai Rd, Xuzhou, 221002, Jiangsu, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.forename: Dandan
authors.initials: D
authors.lastname: Xia
authors.forename: Yueping
authors.initials: Y
authors.lastname: Bian
authors.forename: Yueyue
authors.initials: Y
authors.lastname: Sun
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.forename: Mingshan
authors.initials: M
authors.lastname: Niu
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Wu
authors.forename: Jianlin
authors.initials: J
authors.lastname: Qiao
authors.forename: Chunling
authors.initials: C
authors.lastname: Fu
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.forename: Kailin
authors.initials: K
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000069286:Bortezomib / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D045787:Sesquiterpenes, Eudesmane / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D045787:Sesquiterpenes, Eudesmane; D000069286:Bortezomib; D020169:Caspases; C004363:alantolactone