A novel therapy for lung cancer targeting cancer stem cells.

• Project/Area Number: 23591136
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba University
• Principal Investigator: TAKIGUCHI Yuichi 千葉大学, 医学(系)研究科(研究院), 教授 (30272321)
• Co-Investigator(Renkei-kenkyūsha): KUROSU Katsushi 千葉大学, 大学院医学研究院, 講師 (20291106) ; TADA Yuji 千葉大学, 大学院医学研究院, 講師 (50344990) ; TANABE Nobuhiro 千葉大学, 大学院医学研究院, 教授 (40292700) ; TATSUMI Koichiro 千葉大学, 大学院医学研究院, 教授 (10207061) ; SAKAO Seiichiro 千葉大学, 大学院医学研究院, 講師 (80431740)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: メトホルミン / ゲフィチニブ / 癌幹細胞 / 肺癌 / 細胞株 / アポトーシス / 細胞周期 / シスプラチン

Research Abstract

Cytotoxicity of metformin was elucidated in 4 human lung cancer cell lines. Colonogenicity and cell proliferation were inhibited by metformin in all the cell lines only when the cells were exposed to the metformin for a long period, suggesting its cytostatic characteristics. The combined effects of metformin and gefitinib were examined. It did not suppress the growth of already established tumors, nor did it augment tumor shrinkage by gefitinib. However, it significantly suppressed the regrowth of the tumor after effective treatment with gefitinib, suggesting metformin's specific effect on the residual cells. Its cytotoxicity was characterized by the absence of apoptosis induction and unremarkable cell cycle shift. The residual cells were characterized by enriched cells with high expression of CD133 and CD24. Metformin was still effective on this specific cell population. Targeting residual cells after chemotherapy might represent an effective new strategy for curing cancer.

Research Products

• [Journal Article] Metformin, a Diabetes Drug, Eliminates Tumor-Initiating Hepatocellular Carcinoma Cells. (2013)
  • Author(s): Saito, T., Chiba, T., Yuki, K., Zen, Y., Oshima, M., Koide, S., Motoyama, T., Ogasawara, S., Suzuki, E., Ooka, Y., Tawada, A., Tada, M., Kanai, F., Takiguchi, Y., Iwama, A. and Yokosuka, O.
  • Journal Title: PloS one Volume: 8 Issue: 7 Pages: e70010-e70010
  • DOI: 10.1371/journal.pone.0070010
  • Peer Reviewed
• [Journal Article] Interferon-β Produces Synergistic Combinatory Anti-Tumor Effects with Cisplatin or Pemetrexed on Mesothelioma Cells. (2013)
  • Author(s): Li, Q., Kawamura, K., Yang, S., Okamoto, S., Kobayashi, H., Tada, Y., Sekine, I., Takiguchi, Y., Shingyouji, M., Tatsumi, K., Shimada, H., Hiroshima, K. and Tagawa, M.
  • Journal Title: PloS one Volume: 8 Issue: 8 Pages: e72709-e72709
  • DOI: 10.1371/journal.pone.0072709
  • 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] Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line. (2013)
  • Author(s): Kitazono, S., Takiguchi, Y., Ashinuma, H., Saito-Kitazono, M., Kitamura, A., Chiba, T., Sakaida, E., Sekine, I., Tada, Y., Kurosu, K., Sakao, S., Tanabe, N., Iwama, A., Yokosuka, O. and Tatsumi, K.
  • Journal Title: Int. J. Oncol. Volume: 43 Issue: 6 Pages: 1846-1854
  • DOI: 10.3892/ijo.2013.2120
  • Peer Reviewed
• [Journal Article] CD90 Is a Diagnostic Marker to Differentiate Between Malignant Pleural Mesothelioma and Lung Carcinoma With Immunohistochemistry. (2013)
  • Author(s): Kawamura, K., Hiroshima, K., Suzuki, T., Chai, K., Yamaguchi, N., Shingyoji, M., Yusa, T., Tada, Y., Takiguchi, Y., Tatsumi, K., Shimada, H. and Tagawa, M.
  • Journal Title: Am. J. Clin. Pathol. Volume: 140 Issue: 4 Pages: 544-549
  • DOI: 10.1309/ajcpm2z4ngiipbge
  • Peer Reviewed
• [Journal Article] Lipocalin-2 is associated with radioresistance in oral cancer and lung cancer cells. (2013)
  • Author(s): 椎葉正史、齋藤謙悟、鵜澤一弘
  • Journal Title: International journal of oncology Volume: 42 Issue: 4 Pages: 1197-1204
  • DOI: 10.3892/ijo.2013.1815
  • Peer Reviewed
• [Journal Article] Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines (2012)
  • Author(s): Kitazono-Saitoh M, Takiguchi Y, Sakaida E, Sekine I, Tanabe N, et al
  • Journal Title: Oncology Reports Volume: 28(1) Pages: 33-40
  • DOI: 10.3892/or.2012.1799
  • Peer Reviewed
• [Journal Article] Antiproliferative action of metformin in human lung cancer cell lines (2012)
  • Author(s): Ashinuma H, Takiguchi Y, Sakaida E, Sekine I, et al
  • Journal Title: Oncology Reports Volume: 28(1) Pages: 8-14
  • DOI: 10.3892/or.2012.1763
  • Peer Reviewed
• [Journal Article] Feasibility of cytological diagnosis of sarcoidosis with endobronchial US-guided transbronchial aspiration (2012)
  • Author(s): Kitamura, A., Takiguchi, Y., Kurosu, K., Takigawa, N., Saegusa, F., Hiroshima, K., Nakajima, T., Tanabe, N., Nakatani, Y., Yoshino, I. and Tatsumi, K.
  • Journal Title: Sarcoidosis, Vasculitis, And Diffuse Lung Diseases Volume: 29 Pages: 82-89
  • Peer Reviewed
• [Journal Article] Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed (2012)
  • Author(s): Li, Q., Kawamura, K., Okamoto, S., Yamanaka, M., Yang, S., Yamauchi, S., Fukamachi, T., Kobayashi, H., Tada, Y., Takiguchi, Y., Tatsumi, K., Shimada, H., Hiroshima, K. and Tagawa, M.
  • Journal Title: Cancer Gene Ther Volume: 19 Issue: 3 Pages: 218-228
  • DOI: 10.1038/cgt.2011.86
  • Peer Reviewed
• [Journal Article] Expression of a murine homolog of apoptosis-inducing human IL-24/MDA-7 in murine tumors fails to induce apoptosis or produce anti-tumor effects (2012)
  • Author(s): Nagakawa, Hiroyasu, Shimozato, Osamu, Yu, Ling, Wada, Akihiko, Kawamura, Kiyoko, Li, Quanhai, Chada, Sunil, Tada, Yuji, Takiguchi, Yuichi, Tatsumi, Koichiro and Tagawa, Masatoshi
  • Journal Title: Cellular Immunology Volume: 275 Pages: 90-97
  • Peer Reviewed
• [Journal Article] Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer (2012)
  • Author(s): Ono, M, Tsuda, H, Shimizu, C, Yamamoto, S, Shibata, T, Yamamoto, H, Hirata, T, Yonemori, K, Ando, M, Tamura, K, Katsumata, N, Kinoshita, T, Takiguchi, Y, et al.
  • Journal Title: Breast Cancer Research And Treatment Volume: 132 Pages: 793-805
  • Peer Reviewed
• [Journal Article] Expression of a murine homolog of apoptosis-inducing human IL-24/MDA-7 in murine tumorsfails to induce apoptosis or produce anti-tumor effects (2012)
  • Author(s): Nagakawa H, Shimozato O, Tada Y, Takiguchi Y, Tatsumi K, et al
  • Journal Title: Cellular Immunology Volume: 275(1-2) Issue: 2 Pages: 90-97
  • DOI: 10.1016/j.resinv.2012.04.002
  • Peer Reviewed
• [Journal Article] CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema (2012)
  • Author(s): Shigeta, A., Tada, Y., Wang, J.-Y., Ishizaki, S., Tuyusaki, J., Yamauchi, K., Kasahara, Y., Iesato, K., Tanabe, N., Takiguchi, Y., Sakamoto, A., Tokuhisa, T., Shibuya, K., Hiroshima, K., West, J. and Tatsumi, K.
  • Journal Title: American Journal of Physiology Volume: 303 Issue: 2 Pages: 141-151
  • DOI: 10.1152/ajplung.00337.2011
  • Peer Reviewed
• [Journal Article] Serum hepatocyte growth factor and interleukin-6 are effective prognostic markers for non-small cell lung cancer (2012)
  • Author(s): Ujiie, Hideki, Tomida, Mikio, Akiyama, Hirohiko, Nakajima, Yuki, Okada, Daisuke, Yoshino, Naoyuki, Takiguchi, Yuichi and Tanzawa, Hideki
  • Journal Title: Anticancer Research Volume: 32 Pages: 3251-3258
  • Peer Reviewed
• [Journal Article] E1B-55 kDa-defective adenoviruses activate p53 in mesothelioma and enhance cytotoxicity of anticancer agents (2012)
  • Author(s): Yamanaka, M, Tada, Y, Kawamura, K, Li, Q, Okamoto, S, Chai, K, Yokoi, S, Liang, M, Fukamachi, T, Kobayashi, H, Yamaguchi, N, Kitamura, A, Shimada, H, Hiroshima, K, Takiguchi, Y, et al.
  • Journal Title: Journal Of Thoracic Oncology Volume: 7 Issue: 12 Pages: 1850-1857
  • DOI: 10.1097/jto.0b013e3182725fa4
  • Peer Reviewed
• [Journal Article] Antiproliferative action of metformin in human lung cancer cell lines (2012)
  • Author(s): H Ashinuma, Y Takiguchi, S Kitazono, M Kitazono-Saitoh, A Kitamura, T Chiba, Y Tada, K Kurosu, E Sakaida, I Sekine, N Tanabe, A Iwama, O Yokosuka, K Tatsumi
  • Journal Title: Oncology Reports Volume: in press Issue: 5 Pages: 2118-2126
  • DOI: 10.3892/or_xxxxxxxx
  • Peer Reviewed
• [Journal Article] Characterization of myofibroblasts in chronic thromboembolic pulmonary hypertension (2011)
  • Author(s): Maruoka, Sakao, Kantake, Tanabe
  • Journal Title: Int J Cardiol Volume: 159 Issue: 2 Pages: 119-127
  • DOI: 10.1016/j.ijcard.2011.02.037
  • Peer Reviewed
• [Presentation] Targeting HDACs to overcome cisplatin resistance in malignant plural mesothelioma (2013)
  • Author(s): Baird A, Jennings C, McDonagh L, Flynn L, O'Donnell E, Barr M, Santoni-rugiu E, Hanse F, Kurz T, Takiguchi Y, Thomas W, Zimling Z, O'Byrne, K, Gray S
  • Organizer: Paper presented at : 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney,Australia
• [Presentation] Anti-tumor effects of Ad-p53 on INK4A/ARF-defective mesothelioma are influenced positively by small G protein inhibitors but negatively by heat shock protein 90 inhibitors. Paper presented at : American Society of Gene & Cell Therapy (2013)
  • Author(s): Tagawa M, Chai K, Jiang Y, Kawamura K, Yang S, Ogino A, Yamaguchi N, Kato K, Tada Y, Takiguchi Y, Tatsumi K, Shimada H, Hiroshima K, Kubo S
  • Organizer: 16th Annual Meeting 2013
  • Place of Presentation: Salt Lake, Utah, USA
• [Presentation] Targeting HDACs to overcome cisplatin resistance in malignant plural mesothelioma. (2013)
  • Author(s): Baird, Anne-Marie Jennings, Cormac J McDonagh Lauren Flynn Louise O'Donnell, Eimear Barr, Martin Santoni-rugiu, Eric Hanse, Finn K Kurz, Thomas Takiguchi, Yuichi Thomas, Warren Zimling, Zarah G O'Byrne, Kenneth Gray, Steven
  • Organizer: 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney, Australia
• [Presentation] Anti-tumor effects of Ad-p53 on INK4A/ARF-defective mesothelioma are influenced positively by small G protein inhibitors but negatively by heat shock protein 90 inhibitors. (2013)
  • Author(s): Tagawa, Masatoshi Chai, Kuan Jiang, Yuanyan Kawamura, Kiyoko Yang, Shan Ogino, Atsushi Yamaguchi, Naoto Kato, Kazunori Tada, Yuji Takiguchi, Yuichi Tatsumi, Koichiro Shimada, Hideki Hiroshima, Kenzo Kubo, Shuji
  • Organizer: American Society of Gene & Cell Therapy. 16th Annual Meeting. 2013
  • Place of Presentation: Salt Lake, Utah, USA
• [Presentation] Genome-wide cDNA microarray screening of genes related to pemetrexed resistance in mesothelioma cell lines (2012)
  • Author(s): Sekine I, Kitazono-Saitoh M, Kurimoto R, Sakaida E, Tada Y, Kurosu K, Tatsumi K, Takiguchi Y
  • Organizer: Paper presented at : 5th Asia Pacific Lung Cancer Conference (APLCC)
  • Place of Presentation: Fukuoka
• [Presentation] Anti-proliferative action of metformin on various types of human lung cancer cell lines (2012)
  • Author(s): Ashinuma H, Takiguchi Y, Kitazono S, et al
  • Organizer: Paper presented at : AACR Annual Meeting 2012
  • Place of Presentation: Chicago, USA
• [Presentation] Interaction and cross-resistanced of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines (2012)
  • Author(s): Kitazono M, Takiguchi Y, Kitazono S, et al
  • Organizer: Paper presented at : AACR Annual Meeting 2012
  • Place of Presentation: Chicago, USA
• [Presentation] Effects of metformin on a non-small cell lung cancer cell line with an EGFR mutation (2012)
  • Author(s): Kitazono S, Takiguchi Y, Ashinuma H, et al
  • Organizer: Paper presented at : AACR Annual Meeting
  • Place of Presentation: Chicago, USA
• [Presentation] Zoledronic acid, the third generation of bisphosphonates, produces anti-tumor effects on mesothelioma in vitro and in vivo through apoptosis or S phase arrest in p53-independent and RAS prenylation-independent manners. (2012)
  • Author(s): Tada, Y, Li, Q, Kawamura, K, Kobayashi, H, Sekine, I, Takiguchi, Y, Tatsumi, K, Shimada, H, Hiroshima, K and Tagawa, M
  • Organizer: The 11the International Conference of the International Mesothelioma Interest Group (IMIG 2012)
  • Place of Presentation: Boston, MA, USA
• [Presentation] Reactivation of p53-mediated pathways induces apoptosis in mesothelioma with wild-type p53 gene and produces combinatory synergistic effects with anti-cancer agents. (2012)
  • Author(s): Tagawa, M, Li, Q, Kawamura, K, Shingyoji, M, Tada, Y, Takiguchi, Y, Tatsumi, K, Shimada, H and Hiroshima, K
  • Organizer: The 11the International Conference of the International Mesothelioma Interest Group (IMIG 2012)
  • Place of Presentation: Boston, MA, USA
• [Presentation] ヒト肺癌細胞株に対するmetforminの抗腫瘍効果 (2011)
  • Author(s): 北園聡、芦沼宏典、滝口裕一、他
  • Organizer: 第52回日本肺癌学会総会
  • Place of Presentation: 大阪国際会議場
• [Presentation] 肺癌細胞株を用いたメトホルミンの抗腫瘍効果の検討 (2011)
  • Author(s): 芦沼宏典、北園聡、滝口裕一、他
  • Organizer: 第52回日本肺癌学会総会
  • Place of Presentation: 大阪国際会議場