Molecular analysis of therapeutic effects of angiotensin II type I receptor blocker against castration resistant prostate cancer

• Project/Area Number: 16K08717
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya City University
• Principal Investigator: Takahashi Satoru 名古屋市立大学, 大学院医学研究科, 教授 (60254281)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 去勢抵抗性前立腺癌 / アンギオテンシン受容体阻害剤 / 前立腺癌 / 動物モデル / 転移・浸潤抑制 / アンギオテンシン1型受容体阻害剤 / 去勢抵抗性

Outline of Final Research Achievements

We found that the angiotensin II receptor blocker (ARB), antihypertensive drug, exerted a suppression effects on the growth and progression of rat prostate cancer, and the clinical intervention study revealed that PSA progression was significantly prolonged in prostate cancer patients given an ARB compared with placebo control. Therefore, we examined the effect of ARB on advanced prostate cancer such as castration resistant cancer. We demonstrated that candesartan significantly attenuated both the number and incidence rate per acinus invasive carcinoma development in lateral lobe of rats. Additionally, candesartan administration tended to decrease in size of metastatic lesion in the bone of prostate cancer although there was no significant difference in the incidence of bone metastasis.

Academic Significance and Societal Importance of the Research Achievements

カンデサルタン投与により前立腺癌骨転移の発生頻度に対して効果はみられなかったものの骨転移病巣における癌細胞増殖に対しては抑制傾向が観察された。ヒト前立腺癌において、骨転移巣における癌細胞増殖の制御は骨痛による日常生活動作（Activity of Daily Living, ADL）低下を防ぐ観点から有益な実験結果であり、今後はカンデサルタンが骨内における癌細胞増殖を制御しているメカニズムを解明することが急務な課題であると考える。

Research Products

• [Journal Article] NCL1, a highly selective lysine-specific demethylase 1 inhibitor, suppresses castration-resistant prostate cancer growth via regulation of apoptosis and autophagy. (2019)
  • Author(s): Etani T, Naiki T, Naiki-Ito A, Suzuki T, Iida K, Nozaki S, Kato H, Yagayasu Y, Suzuki S, Kawai N, Yasui T, Takahashi S.
  • Journal Title: J Clin Med Volume: 8 Pages: 442-442
  • DOI: 10.3390/jcm8040442
  • Peer Reviewed / Open Access
• [Journal Article] Cyclohexanone curcumin analogs inhibit the progression of castration-resistant prostate cancer in vitro and in vivo. (2019)
  • Author(s): Mapoung, S., Suzuki, S., Fuji, S., Naiki-Ito, A., Kato, H., Yodkeeree, S., Ovatlarnporn, C., Takahashi, S., Limtrakul, P.
  • Journal Title: Cancer Science Volume: 110 Pages: 596-607
  • DOI: 10.1111/cas.13897
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemopreventive effects of angiotensin II receptor type 2 agonist on prostate carcinogenesis by the down-regulation of the androgen receptor (2018)
  • Author(s): Ito Yusuke、Naiki-Ito Aya、Kato Hiroyuki、Suzuki Shugo、Kuno Toshiya、Ishiguro Yukari、Takahashi Satoru、Uemura Hiroji
  • Journal Title: Oncotarget Volume: 9 Pages: 13859-13869
  • DOI: 10.18632/oncotarget.24492
  • Peer Reviewed / Open Access
• [Journal Article] Early detection of prostate carcinogens by immunohistochemistry of HMGB2 (2018)
  • Author(s): Suzuki Shugo、Kato Hiroyuki、Fuji Satoshi、Naiki Taku、Naiki-Ito Aya、Yamashita Yoriko、Takahashi Satoru
  • Journal Title: J. Toxicol. Sci. Volume: 43 Issue: 6 Pages: 359-367
  • DOI: 10.2131/jts.43.359
  • NAID: 130007384438
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist, Suppresses Rat Prostate Carcinogenesis (2016)
  • Author(s): Suzuki S, Mori Y, Nagano A, Naiki-Ito A, Kato H, Nagayasu Y, Kobayashi M, Kuno T, Takahashi S
  • Journal Title: International Journal of Molecular Sciences Volume: 17 Pages: 2071-2071
  • DOI: 10.3390/ijms17122071
  • Peer Reviewed / Open Access
• [Journal Article] Preventive effects of fermented brown rice and rice bran against prostate carcinogenesis in TRAP rats (2016)
  • Author(s): 4.Kuno T, Nagano A, Mori Y, Kato H, Nagayasu Y, Naiki-Ito A, Suzuki S, Mori H, Takahashi S
  • Journal Title: Nutrients Volume: 8
  • DOI: 10.3390/nu8070421
  • Peer Reviewed / Open Access
• [Journal Article] Histone deacetylase inhibition in prostate cancer triggers miR-320-mediated suppression of the androgen receptor. (2016)
  • Author(s): Sato S, Katsushima K, Shinjo K, Hatanaka A, Ohka F, Suzuki S, Naiki-Ito A, Soga N, Takahashi S, Kondo Y.
  • Journal Title: Cancer Research Volume: 76 Pages: 4192-204
  • DOI: 10.1158/0008-5472.can-15-3339
  • Peer Reviewed / Open Access
• [Presentation] Luteolinの去勢抵抗性前立腺癌に対する抑制効果とandrogen receptor splice variantの役割 (2019)
  • Author(s): 内木綾、加藤寛之、鈴木周五、高橋智
  • Organizer: 第35回日本毒性病理学会総会および学術集会
• [Presentation] A synthetic cyclohexanone curcumin analog, BHMBC, inhibits the progression of castration-resistance prostate cancer. (2018)
  • Author(s): Mapoung,S., Suzuki, S., Fuji, S., Paichamnan, S., Ovatlarnporn, C., Takahashi, S., Limtrakul, P.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 過剰なアンドロゲン曝露は前立腺における異常なDNAメチル化を誘導する (2018)
  • Author(s): 久保絵美、竹島秀幸、山下聡、高橋智、松田恭典、形部憲、牛島俊和
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Chemopreventive effects of angiotensin II receptor type 2 agonist on prostate carcinogenesis by the downregulation of the androgen receptor. (2018)
  • Author(s): Uemura, H., Ito, Y., Naiki-Ito, A., Kato, H., Suzuki, S., Kuno, T., Takahashi, S.
  • Organizer: AACR Annual Meeting
  • Int'l Joint Research
• [Book] 前立腺がん化学予防の現状, 次世代のがん治療薬・診断のための研究開発 (2016)
  • Author(s): 高橋智、鈴木周五、佐藤慎哉、内木綾、久野壽也
  • Publisher: 技術情報協会