Mechanism of docetaxel and cabazitaxel-resistance in castration-resistant prostate cancer

Research Project

Project/Area Number	16K10999
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Urology
Research Institution	Kanazawa University
Principal Investigator	KADONO Yoshifumi 金沢大学, 医学系, 准教授 (10397218)
Co-Investigator(Kenkyū-buntansha)	溝上敦金沢大学, 医学系, 教授 (50248580) 泉浩二金沢大学, 附属病院, 講師 (80646787)
Project Period (FY)	2016-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000) Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords	前立腺癌 / CRPC / ドセタキセル / カバジタキセル / 去勢抵抗性前立腺癌 / 耐性 / ドセタキセル耐性 / カバジタキセル耐性
Outline of Final Research Achievements	The elucidation of the mechanism of the cabazitaxel-resistance and the conquest are important themes to improve the prognosis of the patients. We tried to establish cabazitaxel-resistant CRPC cells and characterized them. We established two cabazitaxel-resistant cells, PC-3-TxR/CxR and DU145-TxR/CxR. PC-3-TxR/CxR and DU145-TxR/ CxR cells became resistant for cabazitaxel by 11.8 and 4.4-fold, respectively. The TxR/CxR cells showed cabazitaxel-resistant using SCID mice in vivo. Expression of MDR1 gene was up-regulated in PC-3-TxR compared with PC-3 cells and was further up-regulated in PC-3-TxR/CxR. Comparison of cDNA microarray between PC-3-TxR and PC-3-TxR/CxR cells or between DU145-TxR and DU145-TxR/CxR cells revealed that many genes were up-regulated or down-regulated. Knockdown of MDR1 recovered the sensitivity to cabazitaxel not only in PC-3-TxR/CxR cells but also DU145-TxR/CxR cells. Together, regulation of MDR1 gene is important for conquest of the cabazitaxel-resistance.
Academic Significance and Societal Importance of the Research Achievements	まず、カバジタキセル耐性株を樹立して、そのキャラクタライズを行えたということは、今後の耐性化克服のための足がかりにあると考えている。また、今回の成果においてMDR1の発現過剰がCRPCのカバジタキセル耐性の機序の一つであるということを明らかにすることができた。MDR1の関与があるということで、MDR1機能を阻害する薬物を併用することによって、抗腫瘍効果を高めたり、副作用の軽減ができる可能性があり、臨床的、社会的に意義があると考えられる。