metastasized site-specific molecular targeted therapy utilizing redox signaling in urothelial carcinoma

• Project/Area Number: 18591752
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Kyoto University
• Principal Investigator: SODA Takeshi Kyoto University, Department of Urology, assistant professor (50422928)
• Co-Investigator(Kenkyū-buntansha): NAWA Osamu Kyoto University, Department of Urology, professor (90260611) ; NISHIYAMA Hiroyuki Kyoto University, Department of Urology, assistant professor (20324642) ; YOSHIMURA Koji Kyoto University, Department of Urology, assistant professor (40397542) ; TAKAHASHI Takeshi Kyoto University, Department of Urology, assistant professor (30362487)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: urothelial carcinoma / chemo resistance / p21 / CDDP / シスプラチン / Redox / Dicoumarol / NQO-1 / 尿路性器癌 / 分子標的治療 / Galectin7 / レドックス / 化学療法 / 転移

Research Abstract

To improve conventional chemotherapeutic-efficacy for the treatment of metastasized urothelial carcinoma, a combination use of traditional medicines is not completely effective and detailed mechanisms have been rarely elucidated. First, we demonstrated that a comprehensive approach for the detection of p53 mutations may be essential to elucidate their clinical significance. In addition to that, 3-30-Methylene-bis [4-hydroxycoumarin] (dicoumarol), an inhibitor of NADPH: quinone oxidoreductase 1, was assessed for its potential antineoplastic effects and the ability to abrogate p53 protein. It is suggested that dicoumarol could enhance cytotoxicity of CDDP in urogenital cancer cells with wild-type p53 through the p53/p21/JNK pathways.
Second, we assessed the possibility of galectin-7 to accelerate CDDP-induced cell killing in vitro and also to predict chemosensitivity against CDDP in urothelial cancer patients. We found that Galectin-7 is a candidate for a predictive marker of chemosensitivity against CDDP, and the targeted expression of galectin-7 might overcome the chemoresistance of urothelial cancer.
Finally, we clarified how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP) -induced cytotoxicity in urothelial cancer cells. It is proven that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.
In the near future these facts obtained from our studies can contribute to establish new strategies of chemotherapy for urothelial carcinoma.

Research Products

• [Journal Article] Development of a multiplex RNA urine test for the detection and stratification of transitional cell carcinoma of the bladder. (2008)
  • Author(s): Holyoake A, O'Sullivan P, Pollock R, Best T, Watanabe J, Kajita Y, Matsui Y, Ito M, Nishiyama H, Kerr N, da Siva Tatley F, Cambridge L, Toro T, Ogawa O, Guilford P.
  • Journal Title: Clin Cancer Res. 14 Pages: 742-749
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3 beta with p53. (2008)
  • Author(s): Matsui Y, Watanabe J, Ikegawa M, Kamoto T, Ogawa O, Nishiyama H.
  • Journal Title: Oncogene. 27 Pages: 1-12
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Development of a multiplex RNA urine test for the detection and stratification of transitional cell carcinoma of the bladder (2008)
  • Author(s): Holyoake, A., O'Sullivan, P., Pollock, R., Best, T., Watanabe, J., Kajita, Y., Matsui, Y., Ito, M., Nishiyama, H., Kerr, N., da, Silva, Tatley, F., Cambridge, L., Toro, T., Ogawa, O., Guilford, P
  • Journal Title: Clin Cancer Res 14(3) Pages: 742-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3 beta with p53 (2008)
  • Author(s): Matsui, Y., Watanabe, J., Ikegawa, M., Kamoto, T., Ogawa, O., Nishiyama, H
  • Journal Title: Oncogene (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genomic characterization of multiple clinical phenotypes of cancer using multivariate linear regression models. (2007)
  • Author(s): Matsui S, Ito M, Nishiyama H, Uno H, Kotani H, Watanabe J, Guilford P, Reeve A, Fukushima M, Ogawa O.
  • Journal Title: Bioinformatics. 97 Pages: 732-738
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Synergy of interferon-alpha and 5-Fluorouracil in human renal cell carcinoma requires p53 activity. (2007)
  • Author(s): Shang D, Ito N, Watanabe J, Awakura Y, Nishiyama H, Kamoto T, Ogawa O.
  • Journal Title: Eur Urol. 52 Pages: 1131-1139
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Sensitizing effect of galectin-7 in urothelial cancer to cisplatin through the accumulation of intracellular reactive oxygen species. (2007)
  • Author(s): Matsui Y, Ueda S, Watanabe J, Kuwabara I, Ogawa O, Nishiyama H.
  • Journal Title: Cancer Res. 67 Pages: 1212-1220
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Genetic analysis of multifocal superficial urthelial cancers by array-based comparative genomic hybridization. (2007)
  • Author(s): Kawanishi H, Takahashi T, Ito M, Matsui Y, Watanabe J, Ito N, Kamoto T, Kadowaki T, Tsujimoto G, Imoto I, Inazawa J, Nishiyama H, Ogawa O.
  • Journal Title: Br J Cancer. 97 Pages: 260-266
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Genomic characterization of multiple clinical phenotypes of cancer using multivariate linear regression models (2007)
  • Author(s): Matsui, S., Ito, M., Nishivama, H., Uno, H., Kotani, H., Watanabe, J., Guilford, P., Reeve, A., Fukushima, M., Ogawa, O
  • Journal Title: Bioinformatics 23(6) Pages: 732-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synergy of interferon-alpha and 5-Fluorouracil in human renal cell carcinoma requires p53 activity (2007)
  • Author(s): Shang, D., Ito, N., Watanabe, J., Awakura, Y., Nishiyama, H., Kamoto, T., Ogawa, O
  • Journal Title: Bur Urol 52(4) Pages: 1131-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sensitizing effect of galectin-7 in urothelial cancer to cisplatin through the accumulation of intracellular reactive oxygen species (2007)
  • Author(s): Matsui, Y., Ueda, S., Watanabe, J., Kuwabara, I., Ogawa, O., Nishiyama, H
  • Journal Title: Cancer Res 67(3) Pages: 1212-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genetic analysis of multifocal superficial urthelial cancers by array-based comparative genomic hybridization (2007)
  • Author(s): Kawanishi, H., Takahashi, T., Ito, M., Matsui, Y., Watanabe, J., Ito, N., Kamoto, T., Kadowaki, T., Tsuiimoto, G., mote, I., Inazawa, J., Nishiyama, H., Ogawa, O
  • Journal Title: Br J Cancer 97(2) Pages: 260-6
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sensitizing effect of galectin-7 in urothelial cancer to cisplatin through the accumulation of intracellular reactive oxygen species. (2007)
  • Author(s): Matsui Y, Ueda S, Watanabe J, Kuwabara I, Ogawa O, Nishiyama H.
  • Journal Title: Cancer Reserch 67 Pages: 1212-20
  • Peer Reviewed
• [Journal Article] Sensitizing effect of galectin-7 in urothelial cancer to cisplatin through the accumulation of intracellular reactive oxygen species. (2007)
  • Author(s): Matsui Y, Ueda S, Watanabe J, Kuwabara I, Ogawa 0, Nishiyama H
  • Journal Title: Cancer Research 67(3) Pages: 1212-1220
• [Journal Article] Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild type urogenital cancer cell lines. (2006)
  • Author(s): Watanabe J, Nishiyama H, Matsui Y, Ito M, Kawanishi H, Kamoto T, Ogawa O.
  • Journal Title: Oncogene. 25 Pages: 2500-2508
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Association of the PIG3 promoter polymorphism with invasive bladder cancer in a Japanese population. (2006)
  • Author(s): Ito M, Nishiyama H, Watanabe J, Kawanishi H, Takahashi T, Kamoto T, Habuchi T. Ogawa O.
  • Journal Title: Jpn J Clin Oncol. 36 Pages: 116-120
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] High throughput comparative genomic hybridization array an alysis of multifocal urothelial cancers. (2006)
  • Author(s): Kawanishi H, Takahashi T, Ito M, Watanabe J, Higashi S, Kamoto T, Habuchi T, Kadowaki T, Tsujimoto G, Nishiyama H, Ogawa O.
  • Journal Title: Cancer Sci. 97 Pages: 746-752
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Dicoumarol potentiates cisplatin-induced apoptosis mediated byc-Jun N-terminal kinase in p53 wild type urogenital cancer cell lines (2006)
  • Author(s): Watanabe, J., Nishivama, H., Matsui, Y., Ito, M., Kawanishi, H., Kamoto, T., Ogawa, 0
  • Journal Title: Oncogene 25(17) Pages: 2500-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of the PIG3 promoter polymorphism with invasive bladder cancer in a Japanese population (2006)
  • Author(s): Ito, M., Nishiyama, H., Watanabe, J., Kawanishi, H., Takahashi, T., Kamoto, T., Habuchi, T., Ogawa, O
  • Journal Title: Jpn J Clin Oncol 36(2) Pages: 116-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High throughput comparative genomic hybridization array analysis of multifocal urothelial cancers (2006)
  • Author(s): Kawanishi, H., Takahashi, T., Ito, M., Watanabe, J., Higashi, S., Kamoto, T., Habuchi, T., Kadowaki, T., Tsujimoto, G., Nishiyama, H., Ogawa, O
  • Journal Title: Cancer Sci 97(8) Pages: 746-52
  • NAID: 10018768276
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines. (2006)
  • Author(s): Watanabe J, Nishiyama H, Matsui Y, Ito M, Kawanishi H, Kamoto T, Ogawa 0
  • Journal Title: Oncogene 25(17) Pages: 2500-2508
• [Presentation] 尿路上皮癌におけるtriptolideを用いた癌特異的p21 target therapyに関する検討 (2008)
  • Author(s): 松井 喜之、西山 博之、渡部 淳、西澤 恒二、梶田 洋一郎、賀本 敏行、小川 修
  • Organizer: 第17回泌尿器科分子・細胞研究会
  • Place of Presentation: 東京
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] トリプトライドによる尿路上皮癌のシスプラチン感受性増強機序の解析 (2007)
  • Author(s): 松井 喜之
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] 尿路上皮癌におけるgalectin7発現による化学療法感受性の制御機構 (2007)
  • Author(s): 松井 喜之、川西 博晃、西山 博之、賀本 敏行、小川 修
  • Organizer: 第95回日本泌尿器科学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2007-04-14
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Triptolide(PG490)-mediated sensitization of urothelial cancer cells tocisplatin-induced apoptosis (2007)
  • Author(s): Yoshiyuki Matsui, Hiroaki Kawanishi, Jun Watanabe, Hiroyuki Nishiyama, Osamu Ogawa
  • Organizer: 2007年米国癌学会(AACR)総会
  • Place of Presentation: ロサンゼルス アメリカ
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] トリプトライド(PG490)による尿路上皮癌のシスプラチン感受性増強機序の解析 (2007)
  • Author(s): 松井 喜之、渡部 淳、賀本 敏行、小川 修、西山 博之
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] P21 attenuating therapy by triptolide(PG490)enhances the cytotoxicity of cisplatin in urothelial cancer cells with wild-type p53 (2007)
  • Author(s): Yoshiyuki Matsui, Osamu Ogawa
  • Organizer: 2007年URS(Urological Research Society)総会
  • Place of Presentation: ナパ アメリカ
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Triptolide (PG490)-mediated sensitization of urothelial cancer cells to cisplatin-induced apoptosis (2007)
  • Author(s): Yoshiyuki, Matsui, Hiroaki, Kawanishi, Jun, Watanabe, Hiroyuki, Nishiyama, Osamu, Ogawa
  • Organizer: 2007 AACR
  • Place of Presentation: Los Angeles, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] P21 attenuating therapy by triptolide (PG490) enhances the cytotoxicity cisplatin in urothelial cancer cells with wild-type p53 (2007)
  • Author(s): Yoshivuki, Matsui, Osamu, Ogawa
  • Organizer: 2007 URS (Urological Research Society)
  • Place of Presentation: Napa, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 尿路上皮癌におけるNQO1修飾による抗癌剤感受性増強機序の解析 (2006)
  • Author(s): 松井 喜之, 西山博之、川西 博晃、高橋 毅、賀本敏行、小川 修
  • Organizer: 第65回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2006-09-29
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Impact of galectin 7 expression on the chemosensitivity of urothelial cancer (2006)
  • Author(s): Yoshiyuki Matsui, Hiroaki Kawanishi, Masaaki Ito, Jun Watanabe, Hiroyuki Nishiyama, Osamu Ogawa, Shugo Ueda^*, Ichiro Kuwabara^<**>, Fu-Tong Liu^<**>
  • Organizer: 2006年米国泌尿器科学会(AUA)総会
  • Place of Presentation: アトランタ アメリカ
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Impact of galectin 7 expression on the chemosensitivity of urothelial cancer (2006)
  • Author(s): Yoshiyuki, Matsui, Hiroaki, Kawanishi, Masaaki, Ito, Jun, Watanabe, Hiroyuki, Nishiyama, Osamu, Ogawa, Shugo, Ueda*, Ichiro, Kuwabara**, Fu-Tong, Liu**
  • Organizer: 2006AUA
  • Place of Presentation: Atlanta, USA
  • Description: 「研究成果報告書概要(欧文)」より