Activation of the p53 pathway by gene medicine and a chemotherapeutic agent produces anti-tumor effects on human mesothelioma cells

• Project/Area Number: 24591185
• 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 Cancer Center (Research Institute)
• Principal Investigator: MASATO Shingyoji 千葉県がんセンター(研究所), その他部局等, その他 (60450433)
• Co-Investigator(Kenkyū-buntansha): TAGAWA Masatoshi 千葉県がんセンター(研究所), がん治療開発グループ, 部長 (20171572)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 悪性中皮腫 / アデノウイルス / p53経路 / アポトーシス / ビスフォスフォネート / siRNA / 細胞死 / 抗がん剤 / E1B / Rb蛋白

Outline of Final Research Achievements

We examined a possible therapeutic strategy for mesothelioma, which is linked with asbestos exposure. A major genetic characteristic of the clinical specimens is a deletion of p14 and p16 genes, which subsequently inactivate the p53 and the pRb pathways. We thereby targeted the p53 pathway and reconstituted the functions by gene transduction with a few kinds of adenovirus vectors. The adenovirally transduced cells showed apoptotic cell death accompany by phosphorylation of p53 and dephosphorylation of pRb. We also found that bisphosphonates, commonly used for malignancy-linked hypercalcemia and for osteoporosis, was highly cytotoxic to mesothelioma. The agent is inhibits prenylation of small G proteins and subsequently suppress the functions. The cells treated with bisphosphonates were subjected to apoptotic cell death with activation of the p53 pathways.

Research Products

• [Journal Article] Fas ligand DNA enhances a vaccination effect by coadministered DNA encoding a tumor antigen through augmenting production of antibody against the tumor antigen. (2015)
  • Author(s): Zhong, B., Ma, G., Sato, A., Shimozato, O., Liu, H., Li, Q., Shingyoji, M., Tada, Y., Tatsumi, K., Shimada, H., Hiroshima, K. and Tagawa, M.
  • Journal Title: J Immunol Res Volume: 2015 Pages: 743828-743828
  • DOI: 10.1155/2015/743828
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Zoledronic acid induces apoptosis and S-phase arrest in mesothelioma through inhibiting Rab family proteins and topoisomerase II actions. (2014)
  • Author(s): Okamoto, S., Jiang, Y., Kawamura, K., Shingyoji, M., Tada, Y., Sekine, I., Takiguchi, Y., Tatsumi, K., Kobayashi, H., Shimada, H., Hiroshima, K. and Tagawa, M.
  • Journal Title: Cell Death Dis Volume: ５ Issue: 11 Pages: e1517-e1517
  • DOI: 10.1038/cddis.2014.475
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Endobronchial ultrasonography for positron emission tomography and computed tomography-negative lymph node staging in non-small cell lung cancer. (2014)
  • Author(s): Shingyoji M, Nakajima T, Yoshino M, Yoshida Y, Ashinuma H, Itakura M, Tatsumi K, Iizasa T
  • Journal Title: Ann Thorac Surg. Volume: 98 Issue: 5 Pages: 1762-1767
  • DOI: 10.1016/j.athoracsur.2014.05.078
  • Peer Reviewed / Open Access
• [Journal Article] Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels. (2013)
  • Author(s): Okamoto, S., Jiang, Y., Kawamura, K., Shingyoji, M., Fukamachi, T., Tada, Y., Takiguchi, Y., Tatsumi, K., Shimada, H., Hiroshima, K., Kobayashi, H. and Tagawa, M.
  • Journal Title: PLoS ONE Volume: 8 Issue: 3 Pages: e60297-e60297
  • DOI: 10.1371/journal.pone.0060297
  • 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] 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] Heat-shock protein 90 inhibitors synergistically enhance melanoma differentiation-associated gene-7-mediated cell killing of human pancreatic carcinoma. (2013)
  • Author(s): Zhang, M., Kawamura, K., Jiang, Y., Shingyoji, M., Ma, G., Li, Q., Hu, J., Qi, Y., Liu, H., Zhang, F., Kang, S., Shan, B., Wang, S., Chada, S. and Tagawa, M.
  • Journal Title: Cancer Gene Ther Volume: 20 Issue: 3 Pages: 663-670
  • DOI: 10.1038/cgt.2013.6
  • 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] Zoledronic acid produces antitumor effects on mesothelioma through apoptosis and S-phase arrest in p53-independent and Ras prenylation-independent manners. (2012)
  • Author(s): Okamoto, S., Kawamura, K., Li, Q., Yamanaka, M., Yang, S., Fukamachi, T., Tada, Y., Tatsumi, T., Shimada, H., Hiroshima, K., Kobayashi, H. and Tagawa, M.
  • Journal Title: J. Thorac. Oncol. Volume: 7 Issue: 5 Pages: 873-882
  • DOI: 10.1097/jto.0b013e31824c7d43
  • 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] 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
• [Presentation] Activation of p53 pathways with adenoviruses bearing the p53 gene and an inhibitor for the interaction between Mdm2 and p53 produces synergistic cytotoxicity in mesothelioma. (2014)
  • Author(s): Masatoshi Tagawa, Takaaki Kozono, Shinya Okamoto, Kengo Shimazu, Masato Shingyoji, Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima.
  • Organizer: 12th international conference of the international mesothelioma interested group
  • Place of Presentation: Cape Town, South Africa
  • Year and Date: 2014-10-21 – 2014-10-24
• [Presentation] アデノウイルス製剤を用いた悪性中皮腫に対する遺伝子治療の実施にむけて (2014)
  • Author(s): 田川雅敏, 多田裕司、新行内雅斗，由佐俊和，島田英昭，廣島健三，巽浩一郎
  • Organizer: 第21回石綿・中皮腫研究会
  • Place of Presentation: 名古屋市熱田区
  • Year and Date: 2014-10-11
• [Presentation] A small molecule that inhibits p53 degradation influences cytotoxicity of Ad-p53 in INK4A/ARF-defective mesothelioma with wild-type p53 gene. (2014)
  • Author(s): Masatoshi Tagawa, Kiyoko Kawamura, Shinya Okamoto, Yuanyuan Jiang, Zhihan Li, Shuji Kubo, Masato Shingyoji, Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: 17th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: Washington DC、USA
  • Year and Date: 2014-05-21 – 2014-05-24
• [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): Masatoshi Tagawa, Kuan Chai, Yuanyuan Jiang, Kiyoko Kawamura, Shan Yang, Atsushi Ogino, Naoto Yamaguchi, Kazunori Kato, Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima and Shuji Kubo
  • Organizer: 16th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: Salt Lake City, USA
• [Presentation] Activation of p53 pathways produces combinatory effects with chemotherapeutic agents on p53 wild-type mesothelioma. (2013)
  • Author(s): Masatoshi Tagawa, Kiyoko Kawamura, Shan Yang, Yuanyuan Jiang, Kuan Chai, Naoto Yamaguchi, Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada and Kenzo Hiroshima
  • Organizer: 19th annual meeting of Japan Society of Gene Therap
  • Place of Presentation: Okayama
• [Presentation] Cytotoxicity of replication-competent adenoviruses are enhanced by co-transduced p53 gene. (2013)
  • Author(s): Masatoshi Tagawa, Shan Yang, Kiyoko Kawamura, Shinya Okamoto, Shuji Kubo, Yuji Tada, Kenzo Hiroshima, Hideaki Shimada
  • Organizer: 21th Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Madrid, Spain
• [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): Masatoshi Tagawa, Quanhai Li, Kiyoko Kawamura, Masato Shingyoji, Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima.
  • Organizer: The11th international conference of the international mesothelioma interested group
  • Place of Presentation: ボストン、米国
• [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): Yuji Tada, Quanhai Li, Kiyoko Kawamura, Hiroshi Kobayashi, Ikuo Sekine, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa.
  • Organizer: The11th international conference of the international mesothelioma interested group
  • Place of Presentation: ボストン、米国
• [Presentation] A small G protein inhibitor, bisphosphonates, produces synergistic cytotoxicity on wild-type p53-bearing mesothelioma with adenoviruses up-regulating the p53 expression level. (2012)
  • Author(s): Masatoshi Tagawa, Kiyoko Kawamura, Shinya Okamoto, Jiang Yuan Yuan, Masato Shingyoji, Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima.
  • Organizer: 20th Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: ベルサイユ、フランス