A novel therapy for lung cancer targeting cancer stem cells.

2013 Fiscal Year Final Research Report

• 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
• 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

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, Yokosuka O
  • Journal Title: PloS one Volume: 8(7) Pages: e70010
  • DOI: 10.1371/journal.pone.0070010
  • Peer Reviewed
• [Journal Article] Interferon-βProduces 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, Tagawa M
  • Journal Title: PloS one Volume: 8(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, Nishio K
  • Journal Title: PloS one Volume: 8(5) Pages: 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, Tatsumi, K
  • Journal Title: International Journal of Oncology Volume: 43(6) Pages: 1846-1854
  • DOI: 10.3892/ijo.2013.2120
  • 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, Kitazono, S, Ashinuma, H, Kitamura, A, Tada, Y, Kurosu, K, Sakaida, E, Sekine, I, Tanabe, N, Tagawa, M, Tatsumi, K
  • 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, Kitazono, S, Kitazono-Saitoh, M, Kitamura, A, Chiba, T, Tada, Y, Kurosu, K, Sakaida, E, Sekine, I, Tanabe, N, Iwama, A, Yokosuka, O, Tatsumi, K
  • Journal Title: Oncology Reports Volume: 28(1) Pages: 8-14
  • DOI: 10.3892/or.2012.1763
  • 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
  • Year and Date: 20131027-30
• [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
  • Year and Date: 20130515-18
• [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
  • Year and Date: 20121125-28
• [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
  • Year and Date: 20120331-0404
• [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
  • Year and Date: 20120331-0404
• [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
  • Year and Date: 20120331-0404