Mechanism of anti-proliferative effect of resveratrol derivatives on cancer cells

• Project/Area Number: 25350979
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical biology
• Research Institution: Kinki University
• Principal Investigator: FUJITA Yoshihiko 近畿大学, 医学部, 医学部講師 (80192730)
• Co-Investigator(Renkei-kenkyūsha): OKAWARA Tadashi 熊本科学保健大学, 保健科学部, 教授 (60040325)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: レスベラトロール / MIF / NFkB / JNK / ROS

Outline of Final Research Achievements

Derivatives of resveratrol (RVD) that is included in several foods such as grape skin exert anti-proliferative effect on cancer-derived cells. The mode of action regarding to this effect was investigated using molecular biological methods. We found that one inflammatory cytokine called “MIF” interacts with a transcription factor “NFKB”, which down-regulates “JNK”, an apoptosis-inducible signal molecule, thereby avoiding apoptosis induced by reactive oxygen species (ROS). RVDs can prevent MIF from performing this cell protecting effect by direct binding to MIF, resulting in apoptosis. Therefore, RVDs could be promising lead compounds for the development of a therapeutic agents to fight against cancer.

Research Products

• [Journal Article] Characterization of the cytotoxic activity of [2] rotaxane (TRO-A0001), a novel supramolecular compound, in cancer cells. (2016)
  • Author(s): Yoshihiko Fujita, Masahiko Kimura, Hiroki Sato, Toshikazu Takata, Nobufumi Ono, Kazuto Nishio
  • Journal Title: Archives of Pharnacal Research Volume: 未定 Issue: 6 Pages: 825-832
  • DOI: 10.1007/s12272-016-0741-9
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Inhibition of beta-catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small cell lung cancer with a T790M mutation (2015)
  • Author(s): Togashi Y, Hayashi H, Terashima M, De Velasco MA, Sakai K, Fujita Y, Tomida S, Nakagawa K, Nishio K
  • Journal Title: Journal of Thoracic Oncology Volume: 10 Issue: 1 Pages: 93-101
  • DOI: 10.1097/jto.0000000000000353
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer. (2015)
  • Author(s): Togashi Y, Kogita A, Sakamoto H, Hayashi H, Terashima M, De Velasco MA, Sakai K, Fujita Y, Tomida S, Kitano M, Okuno K, Kudo M, Nishio K
  • Journal Title: Cancer Letters Volume: 356 Issue: 2 Pages: 819-827
  • DOI: 10.1016/j.canlet.2014.10.037
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Supramolecular Substance, [2] Rotaxane, Induces Apoptosis in Human Molt-3 Acute Lymphoblastic Leukemia Cells. (2015)
  • Author(s): Kimura M, Makio K, Hara K, Hiruma W, Fujita Y, Takata T, Nishio K, Ono N.
  • Journal Title: Drug Res Volume: 未定 Issue: 11 Pages: 614-616
  • DOI: 10.1055/s-0034-1395628
  • Peer Reviewed
• [Journal Article] Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer. (2015)
  • Author(s): Kogita A, Togashi Y (equally first author), Hayashi H, Sogabe S, Terashima M, De Velasco MA, Sakai K, Fujita Y, Tomida S, Takeyama Y, Okuno K, Nakagawa K, Nishio K
  • Journal Title: International Journal of Oncology Volume: 46 Issue: 3 Pages: 1025-1030
  • DOI: 10.3892/ijo.2014.2797
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Performance of a novel KRAS mutation assay for formalin-fixed paraffin embedded tissues of colorectal cancer. (2015)
  • Author(s): Sakai K, Yoneshige A, Ito A, Ueda Y, Kondo S, Nobumasa H, Fujita Y, Togashi Y, Terashima M, De Velasco MA, Tomida S, Nishio K.
  • Journal Title: Springerplus Volume: 4 Issue: 1 Pages: 1-6
  • DOI: 10.1186/2193-1801-4-7
  • Peer Reviewed / Open Access
• [Journal Article] Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal. (2015)
  • Author(s): Togashi Y, Hayashi H, Okamoto K, Fumita S, Terashima M, de Velasco MA, Sakai K, Fujita Y, Tomida S, Nakagawa K, Nishio K
  • Journal Title: Lung Cancer Volume: 88 Issue: 1 Pages: 16-23
  • DOI: 10.1016/j.lungcan.2015.01.027
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Melanoma transition is frequently accompanied by a loss of cytoglobin expression in melanocytes: a novel expression site of cytoglobin. (2014)
  • Author(s): Fujita Y, Koinuma S, Develasco MA, Bolz J, Togashi Y, Terashima M, Hayashi H, Matsuo T, Nishio K.
  • Journal Title: PLOS ONE Volume: 9(4) Issue: 4 Pages: 1-9
  • DOI: 10.1371/journal.pone.0094772
  • Peer Reviewed / Open Access
• [Journal Article] Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer. (2014)
  • Author(s): Togashi Y, Sakamoto H, Hayashi H, Terashima M, de Velasco MA, Fujita Y, Kodera Y, Sakai K, Tomida S, Kitano M, Ito A, Kudo M, Nishio K
  • Journal Title: Molecular Cancer Volume: 13 Issue: 1 Pages: 126-126
  • DOI: 10.1186/1476-4598-13-126
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production. (2014)
  • Author(s): Togashi Y, Arao T, Kato H, Matsumoto K, Terashima M, Hayashi H, de Velasco MA, Fujita Y, Kimura H, Yasuda T, Shiozaki H, Nishio K.
  • Journal Title: Oncotarget Volume: 30 Pages: 2962-2673
  • Peer Reviewed
• [Journal Article] KIAA1199 interacts with glycogen phosphorylase kinase β-subunit (PHKB) to promote glycogen breakdown and cancer cell survival. (2014)
  • Author(s): Terashima M, Fujita Y, Togashi Y, Sakai K, De Velasco MA, Tomida S, Nishio K
  • Journal Title: Oncotarget Volume: 30 Pages: 7040-7050
  • Peer Reviewed
• [Journal Article] Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epitherial-mesenchymal transition. (2014)
  • Author(s): Kogita A, Togashi Y, Hayashi H, Sogabe S, Terashima M, De Velasco MA, Sakai K, Fujita Y, Tomida S, Takeyama Y, Okuno K, Nakagawa K, Nishio K
  • Journal Title: International Journal of Oncology Volume: 45 Issue: 4 Pages: 1430-1436
  • DOI: 10.3892/ijo.2014.2574
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MEK inhibitor for gastric cancer with MEK1 mutations. (2014)
  • Author(s): Sogabe S, Togashi Y (equally fisrt author), Kato H, Kogita A, Mizukami T, Sakamoto Y, Banno E, Terashima M, Hayashi H, De Velasco MA, Sakai K, Fujita Y, Tomida S, Yasuda T, Takeyama Y, Okuno K, Nishio K
  • Journal Title: Molecular Cancer Therapeutics Volume: 13 Issue: 12 Pages: 3098-3106
  • DOI: 10.1158/1535-7163.mct-14-0429
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Single nucleotide polymorphism markers for low-dose aspirin-associated peptic ulcer and ulcer bleeding. (2014)
  • Author(s): Shiotani A, Murao T, Fujita Y, Fujimura Y, Sakakibara T, Nishio K, Haruma K.
  • Journal Title: J Gastroenterol Hepatol Volume: Suppl 4 Issue: S4 Pages: 47-52
  • DOI: 10.1111/jgh.12770
  • Peer Reviewed
• [Journal Article] Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma. (2013)
  • Author(s): Kato H
  • Journal Title: Int J Oncol Volume: 42 Issue: 4 Pages: 1151-8
  • DOI: 10.3892/ijo.2013.1830
  • Peer Reviewed
• [Journal Article] Slug increases sensitivity to tubulin-binding agents via the downregulation of βIII and βIVa-tubulin in lung cancer cells (2013)
  • Author(s): Tamura D, Arao T, Nagai T, Kaneda H, Aomatsu K, Fujita Y, Matsumoto K, De Velasco MA, Kato H, Hayashi H, Yoshida S, Kimura H, Maniwa Y, Nishio W, Sakai Y, Ohbayashi C, Kotani Y, Nishimura Y, Nishio K
  • Journal Title: Cancer Med Volume: ２ Issue: 2 Pages: 144-154
  • DOI: 10.1002/cam4.68
  • Peer Reviewed
• [Journal Article] A microarray-based gene expression analysis to identify diagnostic biomarkers for unknown primary cancer. (2013)
  • Author(s): Kurahashi, I., Fujita, Y., Arao, T., Kurata, T., Koh, Y., Sakai, K., Matsumoto, K., Tanioka, M., Takeda, K., Takiguchi, Y., Yamamoto, N., Tsuya, A., Matsubara, N., Mukai, H., Minami, H., Chayahara, N., Yamanaka, Y., Miwa, K., Takahashi, S., Takahashi, S., Nakagawa, K. and Nishio, K.
  • Journal Title: PloS one Volume: 8 Issue: 5 Pages: e63249-e63249
  • DOI: 10.1371/journal.pone.0063249
  • Peer Reviewed
• [Journal Article] Detection of EGFR T790M mutation in plasma DNA from patients refractory to EGFR tyrosine kinase inhibitor. (2013)
  • Author(s): Sakai, K., Horiike, A., Darryl, I., Keita, K., Fujita, Y., Tanimoto, A., Sakatani, T., Saito, R., Kaburaki, K., Noriko, Y., Ohyanagi, F., Nishio, M., Nishio, K.
  • Journal Title: Cancer Sci. Volume: 104(9) Issue: 9 Pages: 1198-204
  • DOI: 10.1111/cas.12211
  • Peer Reviewed
• [Journal Article] Influence of novel supramolecular substance, [2] rotaxane, on the caspase signaling pathway in melanoma and colon cancer cells in vitro. (2013)
  • Author(s): Hara K, Beppu T, Kimura M, Fujita Y, Takata T, Nishio K, Ono N.
  • Journal Title: J Pharmacol Sci Volume: 122 Pages: 153-157
  • NAID: 10031185408
  • Peer Reviewed
• [Journal Article] The OCT4 pseudogene POU5F1B is amplified and promotes an aggressive phenotype in gastric cancer. (2013)
  • Author(s): Hayashi, H., Arao, T., Togashi, Y., Kato, H., Velasco, MA., Kimura, H., Matsumoto, K., Tanaka, K., Okamoto, I., Ito, A., Yamada, Y., Nakagawa, K., Nishio, K.
  • Journal Title: Oncogene Volume: E-pub ahead or print Issue: 2 Pages: 199-208
  • DOI: 10.1038/onc.2013.547
  • Peer Reviewed / Open Access
• [Journal Article] Novel single nucleotide polymorphism markers for low dose aspirin-associated small bowel bleeding. (2013)
  • Author(s): Shiotani A, Murao T, Fujita Y, Fujimura Y, Sakakibara T, Nishio K, Haruma K.
  • Journal Title: PLoS One Volume: 8 Issue: 12 Pages: e84244-e84244
  • DOI: 10.1371/journal.pone.0084244
  • Peer Reviewed
• [Journal Article] Overexpression of heparan sulfate 6-O-sulfotransferase-2 in colorectal cancer. (2013)
  • Author(s): Hatabe S, Kimura H, Arao T, Kato H, Hayashi H, Nagai T, Matsumoto K, DE Velasco M, Fujita Y, Yamanouchi G, Fukushima M, Yamada Y, Ito A, Okuno K, Nishio K.
  • Journal Title: Mol Clin Oncol Volume: １ Pages: 845-850
  • Peer Reviewed
• [Journal Article] 上皮成長因子受容体遺伝子異常と肺発癌 (2013)
  • Author(s): 藤田至彦、西尾和人
  • Journal Title: 日本臨床増刊号 最新肺癌学 Volume: 増刊 Pages: 135-139
• [Presentation] Melanoma transition is frequently accompanied by a loss of cytoglobin, a putative tumor suppressor, in melanocytes (2015)
  • Author(s): Yoshihiko Fujita, Satoshi Koinuma, Marco De Velasco, Bolz Jan, Yosuke Togashi, Masato Terashima, Hidetoshi Hayashi, Takuya Matsuo, Kazuto Nishio.
  • Organizer: 106th AACR Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Presentation] Melanoma transition is frequently accompanied by a loss of cytoglobin expression in melanocytes: a novel expression site of cytoglobin (2014)
  • Author(s): Yoshihiko Fujita, S. Koinuma, Marco A. De Velasco, Jan Bolz, Y. Togashi, M. Terashima, H. Hayashi, T. Matsuo, K. Nishio
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜(パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] マイクロアレイをもちいた原発不明がんの診断バイオマーカーの探索 (2014)
  • Author(s): 藤田至彦
  • Organizer: 日本癌がん分子標的治療学会学術総会
  • Place of Presentation: 仙台(仙台市情報・産業プラザ)
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] A microarray-based gene expression analysis identified diagnostic biomarkers for unknown primary cancer (2014)
  • Author(s): Yoshihiko Fujita, Issei Kurahashi, Takayasu Kurata, Yasuhiro Koh, Kazuko Sakai, Kazuhiko Nakagawa, Kazuto Nishio
  • Organizer: 全米癌研究学会年次総会
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] A microarray-based gene expression analysis identified diagnostic biomarkers for unknown primary cancer (2014)
  • Author(s): Yoshihiko Fujita, Issei Kurahashi, Takayasu Kurata, Yasuhiro Koh, Kazuko Sakai, Kazuhiko Nakagawa, Kazuto Nishio
  • Organizer: 米国癌学会年会（AACR)
  • Place of Presentation: 米国サンディエゴ市コンベンションセンター
• [Presentation] A Microarray-Based Gene Expression Analysis Identified Diagnostic Biomarkers for Unknown Primary Cancer (2013)
  • Author(s): Yoshihiko Fujita, Issei Kurahashi, Takayasu Kurata, Yasuhiro Koh, Kazuko Sakai, Kazuhiko Nakagawa, Kazuto Nishio
  • Organizer: 欧州がん治療学会（ＥＳＭＯ）
  • Place of Presentation: オランダ、アムステルダム、RAI・コンベンションセンター
• [Presentation] Optimization of multiplex mutation analysis based on minimum amount of lung cancer specimen (2013)
  • Author(s): 冨田秀太、坂井和子、藤田至彦、寺嶋雅人、富樫庸介、デベラスコマルコ、光冨徹哉、中川和彦、西尾和人
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Remarks] Ｄｅｐａｒｔｍｅｎｔ ｏｆ Ｇｅｎｏｍｅ Ｂｉｏｌｏｇｙ
  • URL: http://www.med.kindai.ac.jp/genom/info.html
• [Remarks] 近畿大学医学部ゲノム生物学教室 研究に関するお知らせ
  • URL: http://www.med.kindai.ac.jp/genom/study.html