Targetting aggresome formation in metastatic breast cancer cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08970
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Kazama Hiromi 東京医科大学, 医学部, 助手 (00339350)
• Co-Investigator(Kenkyū-buntansha): 川原 玄理 東京医科大学, 医学部, 准教授 (40743331) ; 宮原 か奈 東京医科大学, 医学部, 講師 (90532391)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 乳癌細胞 / 小胞体ストレス / ROS / HDAC6 / プロテアソーム

Outline of Final Research Achievements

Co-administration of Bortezomib (BTZ), a proteasome inhibitor, and Ricolinostat (RCS), an HDAC6 inhibitor, both of which are used in clinical practice, induced synergistic cell death on breast cancer cell line MDA-MB-231 cells. Real-time ER stress monitoring system and western blotting analysis revealed that co-administration of these drugs enhanced ER stress along with cell death rather than a single treatment. Additionally, we observed increased ROS production by the co-administration and the ROS scavenger administration suppressed the ER stress. These data demonstrated that the co-administration of BTZ and RCS promoted ROS production and ER stress, and caused enhanced cell death.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

転移・再発乳癌は極めて難治性で、新たな治療法や新薬の開発が望まれている。しかし新薬の開発には莫大な予算・時間・リスクが伴い、前臨床から第I～III相臨床試験を経て承認に至る確率は極めて低い。本研究では乳癌細胞に、既存薬のコンビネーションにより、ERストレス負荷をかけ、かつ強力な殺細胞効果を示し、そのメカニズムの一端を明らかにした。この結果を基に、難治性乳癌の治療成績の向上ならびに他の癌細胞でも応用することが出来れば、費用対効果および社会貢献度は極めて高いと考えられる。