2. Academic Validation
  3. Fungal dimeric xanthones as anticancer agents by novelly stimulating sodium-calcium exchanger 1

Fungal dimeric xanthones as anticancer agents by novelly stimulating sodium-calcium exchanger 1

  • Eur J Med Chem. 2025 Jun 5:290:117543. doi: 10.1016/j.ejmech.2025.117543.
Guolong Zhou 1,  Kemin Dong 2,  Xiaoyuan Xu 2,  Ruihong Guo 1,  Gang Li 2,  Jianxin Wang 1,  Liyong Zhou 1,  Shuangzhi Yuan 3,  Hongxiang Lou 4,  Hongmei Li 5,  Hui Dong 1,  Xiaoping Peng 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266071, People's Republic of China.
  • 2 Department of Natural Medicinal Chemistry and Pharmacognosy, School of Pharmacy, Qingdao University, Qingdao, 266071, People's Republic of China.
  • 3 Key Laboratory of Chemical Biology of Ministry of Education, Department of Natural Product Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, People's Republic of China.
  • 4 Department of Natural Medicinal Chemistry and Pharmacognosy, School of Pharmacy, Qingdao University, Qingdao, 266071, People's Republic of China; Key Laboratory of Chemical Biology of Ministry of Education, Department of Natural Product Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, People's Republic of China.
  • 5 Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China.
  • 6 Department of Natural Medicinal Chemistry and Pharmacognosy, School of Pharmacy, Qingdao University, Qingdao, 266071, People's Republic of China. Electronic address: pengxiaoping@qdu.edu.cn.
PMID: 40153930 DOI: 10.1016/j.ejmech.2025.117543
Abstract

Multitude of natural products have the ability to demonstrate inhibitory effects on Cancer cells by regulating ion channels/transporters functions. Eighteen xanthone dimers (Xds), including five new dimers diaporxanthones H, I, J-L (1, 2, and 12-14), were isolated and characterized through co-culture and chemical conversion methods. ECD Cotton effect analyses and chemical communication method provided fundamental role in addressing the challenges of elucidating their absolute configurations. Structure-activity relationship (SAR) analysis showed that eight xanthone-xanthone Xds (2-7, 15 and 16) demonstrated marked cytotoxic effects against gastric Cancer (GC) cell line AGS, with undetectable inhibition on human colon Cancer cells. The anti-proliferative potency of Xds was 2-5 fold higher than positive control drug cisplatin. Mechanistic studies were conducted on a high-yield compound, 12-O-deacetyl-phomoxanthone A (4). Compound 4 activated Na+/CA2+ exchanger 1 (NCX1), thereby causing an increase in cellular CA2+ signaling and subsequent inhibition of the downstream PI3K/Akt/β-catenin pathway, ultimately leading to GC cell death. Like anti-GC, Xds also possessed anti-melanoma activity in vitro and in vivo. We demonstrate Xds have effective cytotoxic actions against GC and melanoma by targeting NCX1/CA2+ signaling in Cancer cells.

Keywords

Chemical conversion; Co-culture; Dimeric xanthones; Gastric cancer; NCX1.

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