title: Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway.
abstract: Multiple myeloma (MM) is a clonal plasma cell disorder affecting the immune system with various systemic symptoms. MM remains incurable even with high dose chemotherapy using conventional drugs, thus necessitating development of novel therapeutic strategies. Gossypol (Gos) is a natural polyphenolic compound extracted from cotton plants, and has been shown to possess anti-neoplastic activity against various tumors. Recent studies have shown that Gos is an inhibitor for Bcl-2 or Bcl-XL acting as BH3 mimetics that interfere interaction between pro-apoptotic BH3-only proteins and Bcl-2/Bcl-XL. Since most of the patients with MM overexpress Bcl-2 protein, we considered Gos might be a promising therapeutic agent for MM. We herein show that Gos efficiently induced apoptosis and inhibited proliferation of the OPM2 MM cell line, in a dose- and time-dependent manner. Gos induced activation of caspase-3 and cytochrome c release from mitochondria, showing mitochondrial dysfunction pathway is operational during apoptosis. Further investigation revealed that phosphorylation of Bcl-2 at serine-70 was attenuated by Gos treatment, while protein levels were not affected. In addition, Mcl-1 was downregulated by Gos. Interestingly, phosphorylation of JAK2, STAT3, ERK1/2 and p38MAPK was inhibited by Gos-treatment, indicating that Gos globally suppressed interleukin-6 (IL-6) signals. Moreover, JAK2 inhibition mimicked the effect of Gos in OPM2 cells including Bcl-2 dephosphorylation and Mcl-1 downregulation. These results demonstrated that Gos induces apoptosis in MM cells not only through displacing BH3-only proteins from Bcl-2, but also through inhibiting IL-6 signaling, which leads to Bcl-2 dephosphorylation and Mcl-1 downregulation.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sadahira
authors.affiliation: Department of Hematology, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan.
authors.forename: Morihiko
authors.initials: M
authors.lastname: Sagawa
authors.affiliation: Department of Hematology, Yokohama Municipal Hospital, Kanagawa 240-8555, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nakazato
authors.affiliation: Department of Laboratory Medicine, Tokyo Electric Power Company Hospital, Tokyo 160-0016, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Hematology, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kizaki
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006072:Gossypol; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D006072:Gossypol