Anti-cancer strategy targeting the energymetabolism of tumor cells surviving alow-nutrient acidic microenvironment

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17685
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Iwai Yuki 東京医科大学, 医学部, 助教 (90743302)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 腫瘍微小環境 / アシドーシス / 低栄養 / ESI-09 / 脱共役

Outline of Final Research Achievements

Acidosis limited the cellular consumption of glucose and ATP, causing tumor cells to enter a metabolically dormant but energetically economic state, which promoted tumor cell survival during glucose deficiency. We identified ESI-09, as an anti-cancer compound that inhibited cancer cells under low-glucose conditions even when associated with acidosis. Bioenergetic studies showed that independent of EPAC inhibition, ESI-09 was a safer mitochondrial uncoupler than a classical uncoupler and created a futile cycle of mitochondrial respiration, leading to decreased ATP production, increased ATP dissipation, and fuel scavenging. Accordingly, ESI-09 exhibited more cytotoxic effects under low-glucose conditions than under normal glucose conditions. ESI-09 was also more effective than actively proliferating cells on quiescent glucose-restricted cells. Cisplatin showed opposite effects. ESI-09 inhibited tumor growth in lung cancer engraft mice.

Free Research Field

呼吸器内科

Academic Significance and Societal Importance of the Research Achievements

腫瘍微小環境におけるアシドーシス、栄養欠乏時の腫瘍細胞の生存促進作用を見出し、ESI-09がアシドーシス、低栄養下での代謝のリプログラミングをすることにより、癌細胞のミトコンドリア脱共役剤であることを示した。通常よりも低いグルコース濃度でより高い細胞毒性を発揮し、ESI-09は従来の化学療法よりも安全であり、腫瘍細胞の微小環境下である、低栄養、アシドーシス下の代謝を標的としており、多くの癌細胞にも適応できる可能性がある。