Polyene phosphatidylcholine enhances the therapeutic response of oxaliplatin in gastric cancer through Nrf2/HMOX1 mediated ferroptosis

Peijie Lei; Lianjing Cao; Hongjun Zhang; Jialei Fu; Xiaojuan Wei; Fei Zhou; Jingjing Cheng; Jie Ming; Haijun Lu; Tao Jiang

doi:10.1016/j.tranon.2024.101911

Polyene phosphatidylcholine enhances the therapeutic response of oxaliplatin in gastric cancer through Nrf2/HMOX1 mediated ferroptosis

Transl Oncol. 2024 May:43:101911. doi: 10.1016/j.tranon.2024.101911. Epub 2024 Feb 19.

Authors

Peijie Lei¹, Lianjing Cao², Hongjun Zhang², Jialei Fu², Xiaojuan Wei², Fei Zhou², Jingjing Cheng², Jie Ming², Haijun Lu³, Tao Jiang⁴

Affiliations

¹ Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China; Department of Medicine, Qingdao University, Qingdao 266000, China.
² Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
³ Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China. Electronic address: Lhj82920608@163.com.
⁴ Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China. Electronic address: jiangtao111@qdu.edu.cn.

Abstract

Oxaliplatin (OXA)-based chemotherapy is one of the first-line treatments for advanced gastric cancer. However, the potential risk for chemotherapy-induced hepatic injury can hinder its effectiveness. Polyene phosphatidylcholine (PPC) is often used as a hepatoprotective agent to counter OXA-induced hepatic injury; however, its impact on the antitumour effectiveness of OXA remains uncertain. Our retrospective study examined 98 patients with stage IV gastric cancer to assess the impact of PPC on progression-free survival (PFS) and disease control rate (DCR). Furthermore, in vitro and in vivo assays were conducted to elucidate the combined biological effects of OXA and PPC (OXA+PPC) on gastric cancer. RNA sequencing, luciferase reporter assays, live/dead cell assays, immunofluorescence, and western blotting were used to identify the activated signalling pathways and downstream factors post OXA+PPC treatment. The findings indicated that PPC served as an independent prognostic factor, correlating with prolonged PFS and improved DCR in patients with gastric cancer. The combination of OXA and PPC significantly inhibited tumour cell growth both in vitro and in vivo. RNA sequencing revealed that OXA+PPC treatment amplified reactive oxygen species and ferroptosis signalling pathways. Mechanistically, OXA+PPC upregulated the expression of haem oxygenase-1 by promoting the nuclear migration of nuclear factor erythroid 2-related factor (Nrf2), thereby enhancing its transcriptional activity. Drug-molecule docking analysis demonstrated that PPC competitively bound to the peptide structural domains of both Nrf2 and Kelch-like ECH-associated protein 1 (KEAP1), accounting for the increased translocation of Nrf2. In conclusion, our study reveals the synergistic antitumour potential of PPC and OXA while protecting patients against hepatic injury. This suggests a promising combined treatment approach for patients with advanced gastric cancer.

Keywords: Ferroptosis; Gastric cancer; Oxaliplatin; Polyene phosphatidylcholine.