Molecular targeted therapy against leukemia stem cells via inhibition of anti-apoptotic proteins

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K08410
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: International University of Health and Welfare
• Principal Investigator: Yoshida Akira 国際医療福祉大学, 医学部, 教授 (80252005)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: アポトーシス / Bcl-2 / Mcl-1 / 幹細胞 / 白血病 / 静止期 / Survivin

Outline of Final Research Achievements

Acute leukemia is characterized by the abnormal growth of blastic cells in the bone marrow. Leukemia stem cells display relative quiescence, similar to other cancer stem cell populations. Quiescent cells are generally insensitive to conventional anticancer agents. In the present research project, we searched the novel drugs which can eliminate cytokinetically quiescent (G0/G1) leukemia cells. We examined the cytotoxic activity of Bcl-2 inhibitor Venetoclax and Mcl-1 inhibitor S63845 against leukemia cells including cytokinetically quiescent (G0/G1) cells. Both Venetoclax and S63845 efficiently killed the quiescent leukemia cells via inhibition of Bcl-2 and Mcl-1 protein function. We observed synergistic killing action on leukemia cells when these drugs were simultaneously used as combination therapy. These unique features of these drugs may be beneficial for the development of new therapeutic strategies to eliminate quiescent leukemia cells.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

難治性の急性白血病患者を治癒に導くためには、幹細胞レベルで白血病細胞を死滅させることが重要であると考えられる。従来型の抗がん薬の多くのものがDNA合成阻害剤として作用するものが多く、このため休止期にある幹細胞に対しては充分な効果を発揮できないと考えられる。抗アポトーシス分子Bcl-2およびMcl-1は難治性白血病の幹細胞において発現が亢進していることが報告されている。今回、我々はBcl-2阻害剤VenetoclaxおよびMcl-1阻害剤S63845が休止期にある白血病細胞に対して殺細胞作用を発揮することを見出した。これらの知見は新規治療法の開発に役立つと考えられる。