title: Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma.
abstract: Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin's B-cell lymphoma and is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1',1'-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated whether pyrrolidinium fullerene in combination with the HSP90 inhibitor (geldanamycin; GA) or valproate, potentiated the cytotoxic effects on PEL cells. Compared to treatment with pyrrolidinium fullerene alone, the addition of low-concentration GA or valproate enhanced the cytotoxic activity of pyrrolidinium fullerene. These results indicate that pyrrolidinium fullerene could be used as a novel therapy for the treatment of PEL.
authors: Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412, Japan.
authors: Tadashi
authors: T
authors: Watanabe
authors: Department of Chemistry, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-0023, Japan.
authors: Shigeo
authors: S
authors: Nakamura
authors: Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu 400-8511, Japan.
authors: Toshiya
authors: T
authors: Ono
authors: Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu 400-8511, Japan.
authors: Sadaharu
authors: S
authors: Ui
authors: Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412, Japan.
authors: Syota
authors: S
authors: Yagi
authors: Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412, Japan.
authors: Hiroki
authors: H
authors: Kagawa
authors: Center of Molecular Biosciences, Tropical Biosphere Research Center, University of the Ryukyus, 1 Senbaru, Nishihara-cho, Okinawa 903-0213, Japan.
authors: Hisami
authors: H
authors: Watanabe
authors: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors: Tomoyuki
authors: T
authors: Ohe
authors: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors: Tadahiko
authors: T
authors: Mashino
authors: Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412, Japan. Electronic address: fuji2@mb.kyoto-phu.ac.jp.
authors: Masahiro
authors: M
authors: Fujimuro
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D037741:Fullerenes / Q000737:chemistry / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D019288:Herpesvirus 8, Human / Q000472:pathogenicity; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism; D014771:Virion / Q000187:drug effects
chemical_list: C000593228:1,1,1',1'-tetramethyl (60)fullerenodipyrrolidinium; D000970:Antineoplastic Agents; D016227:Benzoquinones; D001952:Bridged-Ring Compounds; D061945:Caspase Inhibitors; D037741:Fullerenes; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011759:Pyrrolidines; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D053453:Caspase 9; C001277:geldanamycin
keywords: Akt; Apoptosis; Caspase-9; Fullerene; KSHV; PEL