1. Academic Validation
  2. Targeting ABCB6 with nitidine chloride inhibits PI3K/AKT signaling pathway to promote ferroptosis in multiple myeloma

Targeting ABCB6 with nitidine chloride inhibits PI3K/AKT signaling pathway to promote ferroptosis in multiple myeloma

  • Free Radic Biol Med. 2023 Apr 10;S0891-5849(23)00373-8. doi: 10.1016/j.freeradbiomed.2023.04.003.
Zhao Yin 1 Yiwen Lv 2 Li Deng 2 Guangchao Li 1 Ruiming Ou 1 Lizhi Chen 3 Yangmin Zhu 1 Qi Zhong 1 Zhi Liu 1 Jing Huang 1 Hong Wu 1 Qing Zhang 1 Jia Fei 4 Shuang Liu 5
Affiliations

Affiliations

  • 1 Department of Hematology, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, Guangdong Province, 510317, China.
  • 2 College of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China.
  • 3 Department of Science and Education, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, Guangdong Province, 510317, China.
  • 4 Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou, 510632, China.
  • 5 Department of Hematology, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, Guangdong Province, 510317, China. Electronic address: [email protected].
Abstract

Since multiple myeloma (MM) remains a cureless malignancy of plasma cells to date, it becomes imperative to develop novel drugs and therapeutic targets for MM. We screened a small molecule library comprising 3633 natural product drugs, which demonstrated that Nitidine Chloride (NC), an extract from traditional Chinese medicine Zanthoxylum nitidum. We used Surface Plasmon Resonance-High Performance Liquid Chromatography-Protein Mass Spectrometry (SPR-HPLC-MS), Cellular Thermal Shift Assay (CETSA), molecular docking, and SPR assay to identify the potential targets of NC, in which ABCB6 was the unique target of NC. The effects of ABCB6 on cellular proliferation and drug resistance were determined by CCK8, western blot, flow cytometry, site-mutation cells, transmission electron microscopy, immunohistochemistry staining and xenograft model in vitro and in vivo. NC induced MM cell death by promoting Ferroptosis. ABCB6 is the direct target of NC. ABCB6 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. VGSK was the inferred binding epitope of NC on the ABCB6 protein. In the ABCB6-mutated MM cells, NC did not display Cancer resistance, implying the vital role of ABCB6 in NC's bioactivity. Moreover, the silencing of ABCB6 significantly inhibited MM cell growth. Mechanistically, the direct binding of NC to ABCB6 suppressed PI3K/Akt signaling pathway to promote Ferroptosis. In conclusion, ABCB6 can be a potential therapeutic target and prognostic biomarker in MM, while NC can be considered a novel drug for MM treatment.

Keywords

ABCB6; Drug resistance; Ferroptosis; Multiple myeloma; Nitidine chloride; Target identification.

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