Development and mechanism analysis of small molecules affecting tumor-stromal cell interactions

• Project/Area Number: 15K06888
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: KAWADA Manabu 公益財団法人微生物化学研究会, 微生物化学研究所, 部長 (20300808)
• Co-Investigator(Renkei-kenkyūsha): INOUE Hiroyuki 公益財団法人微生物化学研究会, 微生物化学研究所沼津支所, 研究員 (50601548) ; AMEMIYA Masahide 公益財団法人微生物化学研究会, 微生物化学研究所第1生物活性研究部, 研究員 (10232000) ; YOSHIDA Junjiro 公益財団法人微生物化学研究会, 微生物化学研究所第1生物活性研究部, 上級研究員 (20712706)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 抗がん剤 / がん間質 / 天然物

Outline of Final Research Achievements

We have been finding small molecule modulators of tumor-stromal cell interactions among natural compounds using coculture systems of cancer and stromal cells. Here we report the mechanism of action of intervenolin, a novel compound that we found recently, and a new modulator for the lung tumor-stromal cell interactions. We have found that intervenolin stimulates stromal cells to secrete cancer-growth inhibitory factors. Furthermore, we found activity in an actinomycete culture and isolated 8-azaguanine by coculture system of lung cancer and stromal cells. It is suggested that the action of 8-azaguanine needs the direct contact of cells and is independent on nucleotide metabolism.

Research Products

• [Journal Article] Phenazine carboxylic acid and its derivative induce osteoblast differentiation in preosteoblastic MC3T3-E1 cells but adipocyte differentiation in pluripotent mesenchymal C3H10T1/2 cells. (2017)
  • Author(s): Sakamoto, S., Watanabe, T., Kohda, Y., Iijima, M., Sawa, R., Okada, M., Adachi, H., Nishimura, Y., Kawada, M.
  • Journal Title: J. Antibiot. Volume: 70 Issue: 12 Pages: 1146-1149
  • DOI: 10.1038/ja.2017.129
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Total Synthesis and Stereochemical Revision of Leucinostatin A, a Modulator of Tumor-Stroma Interaction (2017)
  • Author(s): Abe, H.; Ouchi, H.; Sakashita, C.; Kawada, M.; Watanabe, T.; Shibasaki, M.
  • Journal Title: Chem. Eur. J. Volume: 23 Issue: 49 Pages: 11792-11796
  • DOI: 10.1002/chem.201703239
  • Peer Reviewed
• [Journal Article] ATP Depletion Assay Led to the Isolation of New 36-Membered Polyol Macrolides Deplelides A and B from Streptomyces sp. MM581-NF15 (2017)
  • Author(s): Toshifumi Takeuchi , Masaki Hatano, Maya Umekita, Chigusa Hayashi, Shun-ichi Wada, Miho Nagayoshi, Ryuichi Sawa, Yumiko Kubota, Manabu Kawada, Masayuki Igarashi, Masakatsu Shibasaki
  • Journal Title: Organic Letters Volume: 19 Issue: 16 Pages: 4207-7210
  • DOI: 10.1021/acs.orglett.7b01807
  • Peer Reviewed
• [Journal Article] Antipodocalyxin Antibody chPcMab-47 Exerts Antitumor Activity in Mouse Xenograft Models of Colorectal Adenocarcinomas. (2017)
  • Author(s): Kaneko MK, Kunita A, Yamada S, Nakamura T, Yanaka M, Saidoh N, Chang YW, Handa S, Ogasawara S, Ohishi T, Abe S, Itai S, Harada H, Kawada M, Nishioka Y, Fukayama M, Kato Y.
  • Journal Title: Monoclon Antib Immunodiagn Immunother. Volume: 36(4) Issue: 4 Pages: 157-162
  • DOI: 10.1089/mab.2017.0020
  • Peer Reviewed
• [Journal Article] Structures and biological activities of novel 4’-acetylated analogs of chrysomycins A and B. (2017)
  • Author(s): Wada, S., Sawa, R., Iwanami, F., Nsgayoshi, M., Kubota, Y., Iijima, K., Hayashi, C., Shibuya, Y., Hatano, M., Igarashi, M., Kawada, M.
  • Journal Title: J. Antibiot. Volume: 70 Issue: 11 Pages: 1078-1082
  • DOI: 10.1038/ja.2017.99
  • Peer Reviewed
• [Journal Article] Impact of MET inhibition on small-cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway. (2017)
  • Author(s): Taniguchi H, Yamada T, Takeuchi S, Arai S, Fukuda K, Sakamoto S, Kawada M, Yamaguchi H, Mukae H, Yano S.
  • Journal Title: Cancer Sci. Volume: 108 Issue: 7 Pages: 1378-1385
  • DOI: 10.1111/cas.13268
  • Peer Reviewed / Open Access
• [Journal Article] Acremopeptin, a new peptaibol from Acremonium sp. PF1450. (2017)
  • Author(s): M. Iijima, M. Amemiya, R. Sawa, Y. Kubota, T. Kunisada, I. Momose, M. Kawada, M. Shibasaki
  • Journal Title: J. Antibiot. Volume: 70 Issue: 6 Pages: 791-794
  • DOI: 10.1038/ja.2017.15
  • Peer Reviewed
• [Journal Article] Mitochondrial uncoupler exerts a synthetic lethal effect against β-catenin mutant tumor cells. (2017)
  • Author(s): 2.Shikata Y, Kiga M, Futamura Y, Aono H, Inoue H, Kawada M, Osada H, and Imoto M.
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 4 Pages: 772-784
  • DOI: 10.1111/cas.13172
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vibrio japonicas sp. nov., a novel member of the Nereis clade in the genus Vibrio isolated from the coast of Japan. (2017)
  • Author(s): Doi, H., Osawa, I., Adachi, H., Kawada, M.
  • Journal Title: PLoS One Volume: 12 Issue: 2 Pages: e0172164-e0172164
  • DOI: 10.1371/journal.pone.0172164
  • Peer Reviewed
• [Journal Article] A novel monoclonal antibody targeting coxsackie virus and adenovirus receptor inhibits tumor growth in vivo. (2017)
  • Author(s): Kawada, M., Inouea, H., Kajikawa, M., Sugiura, M., Sakamoto, S., Urano, S., Karasawa, C., Usami, I., Futakuchi, M., and Masuda, T.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 40400-40400
  • DOI: 10.1038/srep40400
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] New anti-cancer chemicals Ertredin and its derivatives, regulate oxidative phosphorylation and glycolysis and suppress sphere formation in vitro and tumor growth in EGFRvIII-transformed cells. (2016)
  • Author(s): Atsumi, S., Nosaka, C., Adachi, H., Kimura, T., Kobayashi, Y., Takada, H., Watanabe, T., Ohba, S., Inoue, H., Kawada, M., Shibasaki, M., Shibuya, M.
  • Journal Title: BMC Cancer Volume: 16 Issue: 1 Pages: 496-496
  • DOI: 10.1186/s12885-016-2521-9
  • Peer Reviewed / Open Access
• [Journal Article] Small molecules modulating tumor-stromal cell interactions: new candidates for anti-tumor drugs. (2016)
  • Author(s): Kawada, M.
  • Journal Title: J. Antibiot. Volume: 69 Issue: 6 Pages: 411-414
  • DOI: 10.1038/ja.2016.37
  • Peer Reviewed / Open Access
• [Journal Article] The therapeutic potential of microbial proteasome inhibitors. (2016)
  • Author(s): I. Momose, M. Kawada
  • Journal Title: Int. Immunopharmacol. Volume: 37 Pages: 23-30
  • DOI: 10.1016/j.intimp.2015.11.013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Report on the use of nonclinical studies in the regulatory evaluation of oncology drugs (2016)
  • Author(s): Hayakawa Y, Kawada M, Nishikawa H, Ochiya T, Saya H, Seimiya H, Yao Y, Hayashi M, Kai C, Matsuda A, Naoe T, Ohtsu A, Okazaki T, Saji H, Sata M, Sugimura H, Sugiyama Y, Toi M, Irimura T
  • Journal Title: Cancer Sci Volume: 107(2) Issue: 2 Pages: 189-202
  • DOI: 10.1111/cas.12857
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Androprostamines A and B, the new anti-prostate cancer agents produced by Streptomyces sp. MK932-CF8. (2015)
  • Author(s): Yamazaki Y, Someno T, Igarashi M, Kinoshita N, Hatano M, Kawada M, Momose I, Nomoto A.
  • Journal Title: J. Antibiot. Volume: 68 Issue: 4 Pages: 279-285
  • DOI: 10.1038/ja.2014.135
  • Peer Reviewed / Open Access
• [Journal Article] New metastatic model of human small-cell lung cancer by orthotopic transplantation in mice (2015)
  • Author(s): Shuichi Sakamoto, Hiroyuki Inoue, Shunichi Ohba, Yasuko Kohda, Ihomi Usami, Tohru Masuda, Manabu Kawada and Akio Nomoto
  • Journal Title: Cancer Science Volume: 106 Issue: 4 Pages: 367-374
  • DOI: 10.1111/cas.12624
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Stromal cells positively and negatively modulate the growth of cancer cells: stimulation via the PGE2-TNFα-IL-6 pathway and inhibition via secreted GAPDH-E-cadherin interaction. (2015)
  • Author(s): Kawada, M., Inoue, H., Ohba, S., Yoshida, J., Masuda, T., Yamasaki, M., Usami, I., Sakamoto, S., Abe, H., Watanabe, T., Yamori, T., Shibasaki, M., Nomoto, A.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0119415-e0119415
  • DOI: 10.1371/journal.pone.0119415
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis and Structure–Activity Relationship Study of NBRI16716B, an Antitumor Natural Product (2015)
  • Author(s): Abe, H., Sakashita, C., Kawada, M., Nomoto, A., Watanabe, T., Shibasaki, M.
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 63 Issue: 6 Pages: 463-468
  • DOI: 10.1248/cpb.c15-00200
  • NAID: 130005072098
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed
• [Presentation] がん-間質相互作用に干渉する天然物ロイシノスタチンAの全合成、および類縁体の構造活性相関 (2018)
  • Author(s): 阿部 光, 坂下 千春, 川田 学, 渡辺 匠, 柴﨑 正勝
  • Organizer: 日本薬学会 第138年会
• [Presentation] ATP枯渇活性を有する36員環マクロライドdeplelide A及びBの単離・同定 (2018)
  • Author(s): 竹内 倫文, 波多野 和樹, 梅北 まや, 林 千草, 和田 俊一, 永吉 美穂, 澤 竜一, 久保田 由美子, 川田 学, 五十嵐 雅之, 柴﨑正勝
  • Organizer: 日本薬学会 第138年会
• [Presentation] Intervenolin suppresses gastric cancer cell growth via stromal secreted factors (2017)
  • Author(s): Junjiro Yoshida, Hikaru Abe, Takumi Watanabe, Manabu Kawada
  • Organizer: AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics
  • Int'l Joint Research
• [Presentation] Anti-Helicobacter pylori activity of a novel derivative of intervenolin (2017)
  • Author(s): Manabu Kawada, Tomokazu Ohishi, Hikaru Abe, Chigusa Hayashi, Chiharu Sakashita, Shun-ichi Ohba, Hiroyuki Inoue, Masayuki Igarashi, Takumi Watanabe, and Masakatsu Shibasaki
  • Organizer: AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics
  • Int'l Joint Research
• [Presentation] Intervenolin induces the negative regulation of gastric cancer cell growth via interactions with stromal cells (2017)
  • Author(s): Junjiro Yoshida, Hikaru Abe, Daisuke Tatsuda, Masahide Amemiya, Takumi Watanabe, Manabu Kawada
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Modulation of the lung tumor-stromal cell interactions by 8-azaguanine (2017)
  • Author(s): Manabu Kawada, Masahide Amemiya, Shuichi Sakamoto, Tomokazu Ohishi, Junjiro Yoshida, Daisuke Tatsuda
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 8-azaguanineによる肺がんー間質相互作用を介した肺がん細胞の増殖阻害 (2017)
  • Author(s): 川田学、雨宮昌秀、坂本修一、大石智一、吉田潤次郎、立田大輔
  • Organizer: 第21回日本がん分子標的治療学会学術集会
• [Presentation] Ertredin, a new inhibitor of sphere & tumor growth, regulates mitochondrial respiration and glycolysis in EGFRvIII-transformed cells. (2016)
  • Author(s): Atsumi, S., Nosaka, C., Adachi, H., Kimura, T., Kobayashi, Y., Takada, H., Watanabe, T., Ohba, S., Inoue, H., Kawada, M., Shibasaki, M., Shibuya, M.
  • Organizer: The 21st JFCR-International Symposium on Cancer Chemotherapy (JFCR-ISCC)
  • Place of Presentation: 日本科学未来館（東京都江東区）
  • Year and Date: 2016-12-15
  • Int'l Joint Research
• [Presentation] Intervenolin類縁体による新規ピロリ菌治療戦略の開発 (2016)
  • Author(s): 大石智一、増田徹、安達勇光、林千草、大庭俊一、阿部光、五十嵐雅之、渡辺匠、稲岡健ダニエル、北潔、柴﨑正勝、川田学、
  • Organizer: 第37回日本臨床薬理学会学術総会
  • Place of Presentation: 米子コンベンションセンター（鳥取県米子市）
  • Year and Date: 2016-12-02
• [Presentation] Inhibition of osteosarcoma cell growth by geraniin in vivo (2016)
  • Author(s): Tatsuda, D., Momose, I., Ohba, S., Umezawa, Y., Kawada, M., Shibasaki, M.
  • Organizer: 28th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium
  • Place of Presentation: ICM International Congress Center Munich, Munich (Germany)
  • Year and Date: 2016-12-02
  • Int'l Joint Research
• [Presentation] Mechanism of action of a novel anti-tumor antibody, anti-CXADR 6G10A (2016)
  • Author(s): Kawada, M., Inoue, H., Kajikawa, M., Sugiura, M., Sakamoto, S., Urano, S., Karasawa, C., Usami, I., Futakuchi, M.
  • Organizer: 28th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium
  • Place of Presentation: ICM International Congress Center Munich, Munich (Germany)
  • Year and Date: 2016-12-02
  • Int'l Joint Research
• [Presentation] Intervenolin, a novel compound, induces the suppression of gastric cancer cells by stromal cells via secreted factors (2016)
  • Author(s): Yoshida, J., Amemiya, M., Masuda, T., Kawada, M.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-08
• [Presentation] Anti-Helicobactor pylori activity of a novel derivative of intervenolin (2016)
  • Author(s): Ohishi, T., Masuda, T., Adachi, H., Kawada, M.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-08
• [Presentation] Mechanism of action of anti-CXADR 6G10A, a novel anti-tumor antibody (2016)
  • Author(s): Kawada, M., Kajikawa, M., Sakamoto, S.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-07
• [Presentation] Papyracillic acid and penicillic acid show preferential cytotoxicity under nutrient-deprived conditions (2016)
  • Author(s): Momose, I., Adachi, H., Kawada, M.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] p53-dependent growth suppression of cancer cells by coccoquinones (2016)
  • Author(s): Tatsuda, D., Kawada, M., Momose, I.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Ertredin, a new inhibitor of sphere and tumor growth regulates OXPHOS and glycolysis in EGFRvIII-transformed cells (2016)
  • Author(s): Atsumi, S., Kawada, M., Shibuya, M.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 小細胞肺癌の自然転移モデルの開発とその応用 (2016)
  • Author(s): 坂本修一、川田学
  • Organizer: 第２５回日本がん転移学会学術集会・総会
  • Place of Presentation: 米子コンベンションセンター（鳥取県米子市）
  • Year and Date: 2016-07-21
• [Presentation] Intervenolin誘導体によるピロリ菌抑制効果の検討 (2016)
  • Author(s): 大石智一、大庭俊一、増田徹、雨宮昌秀、川田学
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-06-01
• [Presentation] p53依存的な細胞増殖を阻害する新規アンスラキノン化合物 (2016)
  • Author(s): 立田大輔、百瀬 功、川田学
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-31
• [Presentation] 新規化合物intervenolinによる間質細胞の分泌因子を介した胃がん細胞の増殖抑制 (2016)
  • Author(s): 吉田潤次郎、雨宮昌秀、大庭俊一、増田徹、川田学
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-31
• [Presentation] 低分子化合物Ertredin誘導体によるEGFRvIII発現細胞の3D-sphere形成阻害と腫瘍形成抑制 (2016)
  • Author(s): 渥美園子、川田学、澁谷正史
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-31
• [Presentation] 新規抗がん抗CXADR抗体6G10Aの作用機構の解析 (2016)
  • Author(s): 川田学、梶川益紀
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-31
• [Presentation] Papyracillic acidおよびpenicillic acidによる栄養飢餓選択的細胞毒性 (2016)
  • Author(s): 百瀬功、安達勇光、川田学
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-31
• [Presentation] Stromal cells suppress cancer development by secreted GAPDH-E-cadherin interaction (2015)
  • Author(s): Manabu Kawada, Junjiro Yoshida, Hiroyuki Inoue, Shun-ichi Ohba, Manabu Yamasaki, Ihomi Usami, Shuichi Sakamoto, Hikaru Abe, Takumi Watanabe, Akio Nomoto, Masakatsu Shibasaki
  • Organizer: 27th AACR- NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: Hynes Convention Center, Boston (U.S.A.)
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] 間質細胞が分泌するGAPDHによるがん細胞の増殖抑制 (2015)
  • Author(s): 川田 学、吉田潤次郎、坂本修一、増田 徹
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県）
  • Year and Date: 2015-10-10
• [Presentation] 間質細胞によるGAPDHの分泌を介したがん細胞の増殖制御 (2015)
  • Author(s): 川田 学、坂本修一
  • Organizer: 第24回日本がん転移学会学術集会
  • Place of Presentation: シティプラザ大阪（大阪府）
  • Year and Date: 2015-07-24
• [Presentation] GAPDHの分泌を介した間質細胞によるがん細胞の増殖抑制 (2015)
  • Author(s): 川田 学、吉田潤次郎、大庭俊一、増田 徹
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山全日空ホテル（愛媛県）
  • Year and Date: 2015-06-11
• [Book] 別冊BIO Clinica 慢性炎症とがん (2016)
  • Author(s): 川田 学、吉田潤次郎
  • Publisher: 北隆館
• [Book] 実験医学 (2015)
  • Author(s): 川田 学、吉田潤次郎
  • Publisher: 羊土社
• [Remarks] 微生物化学研究会HP
  • URL: http://www.bikaken.or.jp
• [Remarks] 微生物化学研究所
  • URL: http://www.bikaken.or.jp