Development of novel treatment against refractory oral cancer by uptake inhibition of iron or induction of ferroptosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K09814
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Yamaguchi University
• Principal Investigator: HARADA Koji 山口大学, 大学院医学系研究科, 講師 (60253217)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: デフェロキサミン / アルテスネイト / フェロトーシス / セタキシマブ / GPX4 / 4HNE / 難治性口腔癌

Outline of Final Research Achievements

In the present study, we investigated the novel therapy for refractory oral cancer by the regulation of iron content in cancer cells. Deferoxamine and artesunate　suppressed the proliferation of oral squamous cell carcinoma (OSCC) cells. In addition, we examined the effect of combined treatment between artesunate and existing anticancer agents. Combined treatment of artesunate and cetuximab could suppress cell proliferation markedly by inducing ferroptosis through the reduced expression of GPX4 and enhanced expression of 4HNE. In our in vivo experiment, HSC2 tumor-bearing nude mice were treated with artesunate and/or cetuximab. Tumor growth was significantly suppressed by artesunate and cetuximab combined treatment when compared to artesunate or cetuximab alone, or the control. Our findings indicate that the combination of artesunate and cetuximab might be a promising option for refractory oral cancer treatment because combined therapy artesunate and cetuximab was safe and effective.

Free Research Field

口腔外科

Academic Significance and Societal Importance of the Research Achievements

従来の抗癌剤や分子標的薬とは異なる作用、すなわちデフェロキサミンは癌細胞の鉄の取り込みそのものを制限するもので、アルテスネイトは癌細胞の鉄分の取り込みの多さを利用してフェロトーシスという新規細胞死を誘導して選択的抗癌効果を発揮するものであり、既存の治療法では有効性が無かった難治性口腔癌に対して有効性が期待できる治療法となり得ることが確認できた。また動物実験では重篤な副作用の出現なく、既存の治療法と同以上の抗腫瘍効果が得られ、アルテスネイトと分子標的薬セタキシマブとの併用療法は、さらに安全性と有効性が期待できたため、今後の有用な治療手段の一つとして期待できる。