Possibility of a new synthetics from lamellarins: anti-leukemic and integrase-inhibitory effects against HTLV-1-related leukemia cells.

• Project/Area Number: 23590641
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Nagasaki University
• Principal Investigator: HASEGAWA Hiroo 長崎大学, 大学病院, 講師 (00398166)
• Co-Investigator(Kenkyū-buntansha): IWAO Masatomo 長崎大学, 工学部, 教授 (00100892) ; 上平 憲 長崎大学, 医歯(薬)学総合研究科, 教授 (80108290)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 抗HTLV-1薬 / 分子標的治療薬 / 成人T細胞白血病 / 新規抗がん剤 / 抗ウィルス薬

Research Abstract

Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, has promising anti-tumor activity. It is also reported that lamellarin alpha 20-sulfate inhibits HIV-1 integrase. In the present study, we investigated anti-tumor activity against HTLV-1 related leukemia cell lines and activity of integrase inhibition of HTLV-1 by using new synthesis of lamellarins. We focused on an agent No.5, a new synthetics from lamellarins, that showed potent anti-tumor activity against HTLV-1 related leukemia cell lines and ATL cells but no harm to PBMCs from healthy donors. Microarray analysis indicated that unique apoptosis-related genes were up-regulated by the No.5 agent. We still continue investigating the mechanisms of apoptotic pathways as well as function of integrase inhibition caused by a new synthetics from lamellarins.

Research Products

• [Journal Article] Relevance of molecular tests for HTLV-1 infection as confirmatory tests after the first sero-screening (2014)
  • Author(s): Ishihara K, Inokuchi N, Tsushima Y, Tsuruda K, Morinaga Y, Hasegawa H, Yanagihara K, Kamihira S
  • Journal Title: J Immunoassay Immunochem Volume: 35(1) Pages: 74-82
  • NAID: 120006986762
• [Journal Article] Use of diagnostic and therapeutic biomarkers in personalized oncology based on adult T-cell leukemia/lymphoma research (2013)
  • Author(s): Hasegawa H, Kamihira S
  • Journal Title: Personalized Medicine Universe Volume: 2 Pages: 7-11
• [Journal Article] Transient proliferation of donor-derived ATL cell-like lymphocytes early after allogeneic stem cell transplantation in an adult T-cell leukemia/lymphoma patient (2013)
  • Author(s): Taguchi M, Imaizumi Y, Taguchi J, Imanishi D, Sasaki D, Hasegawa H, Tsushima H, Hata T, Miyazaki Y
  • Journal Title: Blood Volume: 121(21) Pages: 4428-30
• [Journal Article] Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice (2013)
  • Author(s): Ikebe E, Kawaguchi A, Tezuka K, Taguchi S, Hirose S, Matsumoto T, Mitsui T, Senba K, Nishizono A, Hori M, Hasegawa H, Yamada Y, Ueno T, Tanaka Y, Sawa H, Hall W, Minami Y, Jeang KT, Ogata M, Morishita K, Hasegawa H, Fujisawa J, Iha H
  • Journal Title: Blood Cancer J Volume: 3
  • NAID: 120006986112
• [Journal Article] 成人T細胞白血病の細胞免疫形質診断へのアプローチ (2013)
  • Author(s): 鶴田一人,長谷川寛雄,佐々木大介,森沙耶香,濵﨑典子,松野貴子,本村裕美子,渕上麻衣,岡本南,津島裕子,西村典孝,木下知美,森勇人,松本成良,宇野直輝,森永芳智,上平憲,栁原克紀
  • Journal Title: Cytometry Research Volume: 23(2) Pages: 23-31
  • NAID: 10031201111
• [Journal Article] Relationships of diverse apoptotic death process patterns to mitochondrial membrane potential (Δψ(m)) evaluated by three-parameter flow cytometric analysis. (2013)
  • Author(s): Suzuki Y, Hasegawa H, Tsuji T,et al
  • Journal Title: Cytotechnology Volume: 65(1) Issue: 1 Pages: 59-70
  • DOI: 10.1007/s10616-012-9455-0
  • Peer Reviewed
• [Journal Article] Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice. (2013)
  • Author(s): Ikebe E, Kawaguchi A, Tezuka K, et al
  • Journal Title: Blood Cancer Journal Volume: 3 Issue: 8 Pages: e132-e132
  • DOI: 10.1038/bcj.2013.30
  • Peer Reviewed
• [Journal Article] Heterogeneity in clonal nature in the smoldering subtype of adult T-cell leukemia : continuity from carrier status to smoldering ATL (2012)
  • Author(s): Kamihira S, Iwanaga M, Doi Y, Sasaki D, Mori S, Tsurda K, Nagai K, Uno N, Hasegawa H, Yanagihara K, Morinaga Y, Tsukasaki K, Taniguchi H
  • Journal Title: Int J Hematol Volume: 95(4) Pages: 399-408
  • NAID: 10030632587
• [Journal Article] Impact of miR-155 and miR-126 as novel biomarkers on the assessment of disease progression and prognosis in adult T-cell leukemia (2012)
  • Author(s): Ishihara K, Sasaki D, Tsuruda K, Inokuchi N, Nagai K, Hasegawa H, Yanagihara K, Kamihira S
  • Journal Title: Cancer Epidemiol Volume: 36(6) Pages: 560-5
• [Journal Article] Impact of miR-155 and miR-126 as novel biomarkers on the assessment of disease progression and prognosis in adult T-cell leukemia. (2012)
  • Author(s): Ishihara K, Sasaki D, Tsuruda K, et al
  • Journal Title: Cancer Epidemiology Volume: 36(6) Issue: 6 Pages: 560-565
  • DOI: 10.1016/j.canep.2012.07.002
  • Peer Reviewed
• [Journal Article] Heterogeneity in clonal nature in the smoldering subtype of adult T-cell leukemia: continuity from carrier status to smoldering ATL (2012)
  • Author(s): Kamihira S, Iwanaga M, Doi Y, Sasaki D, Mori S, Tsuruda K, Nagai K, Uno N, Hasagawa H, Yanagihara K, Morinaga Y, Tsukasaki K Taniguchi H
  • Journal Title: Int J Hematol Volume: 95 Issue: 4 Pages: 399-408
  • DOI: 10.1007/s12185-012-1020-2
  • NAID: 10030632587
  • Peer Reviewed
• [Journal Article] Paradoxical expression of IL-28B mRNA in peripheral blood in human T-cell leukemia virus Type-1 mono-infection and co-infection with hepatitis C Virus. (2012)
  • Author(s): Kamihira S, Usui T, Ichikawa T et al
  • Journal Title: Virology Journal Volume: 15(9) Issue: 1 Pages: 40-40
  • DOI: 10.1186/1743-422x-9-40
  • Peer Reviewed
• [Journal Article] Aberrant overexpression of membrane-associated mucin contributes to tumor progression in adult T-cell leukemia/lymphoma cells (2011)
  • Author(s): Hasegawa H, Komoda M, Yamada Y, Yonezawa S, Tsutsumida H, Nagai K, Atogami S, Tsuruda K, Osaka A, Sasaki D, Yanagihara K, Imaizumi Y, Tsukasaki K, Miyazaki Y, Kamihira S
  • Journal Title: Leuk Lymphoma Volume: 52(6) Pages: 1108-17
  • NAID: 120006984995
• [Journal Article] LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway (2011)
  • Author(s): Hasegawa H, Yamada Y, Tsukasaki K, Mori N, Tsuruda K, Sasaki D, Usui T, Osaka A, Atogami S, Ishikawa C, Machijima Y, Sawada S, Hayashi T, Miyazaki Y, Kamihira S
  • Journal Title: Leukemia Volume: 25(4) Pages: 575-87
• [Journal Article] Overexpression of Enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy (2011)
  • Author(s): Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, Mano H, Marquez VE, Hayashi T, Yanagihara K, Moriwaki Y, Miyazaki Y, Kamihira S, Yamada Y
  • Journal Title: Haematologica Volume: 96(5) Pages: 712-9
• [Journal Article] (2011)
  • Author(s): Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, Mano H, Marquez VE,Hayashi T, Yanagihara K, Moriwaki Y,Miyazaki Y, Kamihira S, Yamada Y,
  • Journal Title: Haematologica Volume: 96 Issue: 5 Pages: 712-719
  • DOI: 10.3324/haematol.2010.028605
  • Peer Reviewed
• [Journal Article] LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway (2011)
  • Author(s): Hasegawa H, Yamada Y, Tsukasaki K, Mori N, Tsuruda K, Sasaki D, Usui T, Osaka A, Atogami S, Ishikawa C, Machijima Y, Sawada S, Hayashi T, Miyazaki Y, Kamihira S
  • Journal Title: Leukemia Volume: 25 Issue: 4 Pages: 575-587
  • DOI: 10.1038/leu.2010.315
  • NAID: 120006984803
  • Peer Reviewed
• [Journal Article] Aberrant overexpression of membrane-associatedmucin contributes to tumor progression in adult T-cell leukemia/lymphoma cells (2011)
  • Author(s): Hasegawa H, Komoda M, Yamada Y, Yonezawa S, Tsutsumida H, Nagai K, Atogami S, Tsuruda K, Osaka A, Sasaki D, Yanagihara K, Imaizumi Y, Tsukasaki K, Miyazaki Y, Kamihira S
  • Journal Title: Leuk Lymphoma Volume: 52 Issue: 6 Pages: 1108-1117
  • DOI: 10.3109/10428194.2011.559671
  • Peer Reviewed
• [Presentation] 成人T細胞白血病リンパ腫に対するHSP 90阻害薬NVP-AUY922の抗腫瘍効果 (2013)
  • Author(s): 谷口広明、長谷川寛雄、佐々木大介、安東恒史、澤山靖、今西大介、今泉芳孝、田口潤、波多智子、塚崎邦弘、森直樹、栁原克紀、宮崎泰司
  • Organizer: 第6回HTLV-1研究会・シンポジウム
  • Place of Presentation: 東京
• [Presentation] 成人T細胞白血病リンパ腫に対するHeat shock protein 90阻害薬NVP-AUY922の抗腫瘍効果 (2013)
  • Author(s): 谷口広明、長谷川寛雄、今泉芳孝、塚崎邦弘、森直樹、宮崎泰司
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] EZH2阻害剤DZNepはATL細胞のBCL2発現を抑制しアポトーシスを誘導する (2013)
  • Author(s): 佐々木大介、長谷川寛雄、今泉芳孝、宮崎泰司、上平憲
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Heat Shock Protein 90 Inhibitor NVP-AUY922 Has Potent Anti-Tumor Activity With Adult T-Cell Leukemia-Lymphoma Cells (2013)
  • Author(s): Hiroaki Taniguchi, Hiroo Hasegawa, Daisuke Sasaki, Koji Ando, Yasushi Sawayama, Yoshitaka Imaizumi, Daisuke Imanishi, Jun Taguchi, Tomoko Hata, Kunihiro Tsukasaki, Katsunori Yanagihara, , Naoki Mori, and Yasushi Miyazaki
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: NewOrleans, LA, USA
• [Presentation] EZH2 Inhibitor DZNep Induces Apoptosis In Adult T-Cell Leukemia/Lymphoma Cells By BCL2 Suppression Via Regulation Of Mir-181a (2013)
  • Author(s): Sasaki Daisuke, Hasegawa Hiroo, Taniguchi Hiroaki, Yoshitaka Imaizumi, Uno Naoki, Morinaga Yoshitomo, Yasushi Miyazaki, and Yanagihara Katsunori
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: NewOrleans, LA, USA
• [Presentation] 成人T 細胞白血病リンパ腫に対するHeat shock protein 90 阻害薬NVP-AUY922 の抗腫瘍効果 (2013)
  • Author(s): 谷口広明、長谷川寛雄、今泉芳孝、塚崎邦弘、森直樹、宮崎泰司
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] EZH2 阻害剤DZNep はATL 細胞のBCL2 発現を抑制しアポトーシスを誘導する (2013)
  • Author(s): 佐々木大介、長谷川寛雄、今泉芳孝、宮崎泰司、上平憲
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Heat Shock Protein 90 Inhibitor NVP-AUY922 Has Potent Anti-Tumor Activity With Adult T-Cell Leukemia-Lymphoma Cells (2013)
  • Author(s): Hiroaki Taniguchi, Hiroo Hasegawa, Daisuke Sasaki, et al
  • Organizer: 55th American Society of Hematology Annual Meeting,
  • Place of Presentation: NewOrleans, LA, USA
• [Presentation] EZH2 Inhibitor DZNep Induces Apoptosis In Adult T-Cell Leukemia/Lymphoma Cells By BCL2 Suppression Via Regulation Of Mir-181a (2013)
  • Author(s): Daisuke Sasaki, Hiroo Hasegawa, Hiroaki Taniguchi, et al
  • Organizer: 55th American Society of Hematology Annual Meeting,
  • Place of Presentation: NewOrleans, LA, USA
• [Presentation] HTLV-1感染細胞の早期腫瘍バイオマーカーとしてのCD26抗原 (2012)
  • Author(s): 長谷川寛雄、塚崎邦弘、宮崎康司、上平憲
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] CD26 antigen act as a predictive biomarker in the evolution from early to overt smoldering ATL (2012)
  • Author(s): 長谷川寛雄、鶴田一人、佐々木大介、森沙耶香、土井裕子、石原香織、長井一浩、栁原克紀、塚崎邦弘、宮崎康司、上平憲
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都