2. Academic Validation
  3. Design, synthesis, and in vitro and in vivo anti-drug resistant cervical cancer activity of novel licochalcone A derivatives based on dual targeting of VEGFR-2/P-gp

Design, synthesis, and in vitro and in vivo anti-drug resistant cervical cancer activity of novel licochalcone A derivatives based on dual targeting of VEGFR-2/P-gp

  • Bioorg Chem. 2025 May 28:163:108639. doi: 10.1016/j.bioorg.2025.108639.
Zheng Yang 1,  Zhengye Liu 2,  Mourboul Ablise 3,  Juan Jia 4,  Aikebaier Maimaiti 2,  Zhi-Yuan Lv 2,  Zuohelaguli Mutalipu 5,  Tong Yan 2,  Yu Wang 2,  Aizitiaili Aihaiti 2,  Jinyao Li 6,  Zhijian Li 7,  Shixia Huo 8
Affiliations

Affiliations

  • 1 Uygur Medical Hospital of Xinjiang Uygur Autonomous Region(The Second People's Hospital of Xinjiang Uygur Autonomous Region), Urumqi Xinjiang Uygur Autonomous Region, 830049, China; Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang 830017, China; Kashgar Vocational and Technical College, Kashgar, Xinjiang 844000, China; The Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi Xinjiang, 830011, China.
  • 2 The Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi Xinjiang, 830011, China.
  • 3 The Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi Xinjiang, 830011, China. Electronic address: mourboul@xjmu.edu.cn.
  • 4 Kashgar Prefecture Maternal and Child Healthcare Family Planning Service Center, Kashgar, Xinjiang 844000, China.
  • 5 Department of Gynecological Radiation Therapy II Ward, The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Urumqi, Xinjiang 830011, China.
  • 6 Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang 830017, China.
  • 7 Uygur Medical Hospital of Xinjiang Uygur Autonomous Region(The Second People's Hospital of Xinjiang Uygur Autonomous Region), Urumqi Xinjiang Uygur Autonomous Region, 830049, China; The Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi Xinjiang, 830011, China. Electronic address: lizhijian0220@sina.com.
  • 8 Uygur Medical Hospital of Xinjiang Uygur Autonomous Region(The Second People's Hospital of Xinjiang Uygur Autonomous Region), Urumqi Xinjiang Uygur Autonomous Region, 830049, China; The Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, College of Pharmacy, Xinjiang Medical University, Urumqi Xinjiang, 830011, China. Electronic address: huoshixia1983@163.com.
PMID: 40451014 DOI: 10.1016/j.bioorg.2025.108639
Abstract

Targeting the VEGF/VEGFR-2 signaling pathway is considered to be an effective strategy for the treatment of cervical Cancer, and multidrug resistance in cervical Cancer has now been widely demonstrated to be caused by the upregulation of P-gp. This study designed and synthesized a series of novel licochalcone A derivatives using licochalcone A as the lead compound and VEGFR-2 and P-gp as the action targets. The principle of active substructure splicing was employed to design and synthesize a series of novel licochalcone A derivatives and to preliminarily evaluate the in vitro and ex vivo anti-cancer active effects of the target compounds. The results showed that the IC50 values of candidate compound A20 against HeLa and HeLa/DDP cells were 3.19 ± 0.08 and 3.69 ± 0.53 μΜ, respectively, with a resistance index (RI) of 1.16, and there was showed minimal development of resistance. In addition, A20 was able to form a hydrogen bonding force with VEGFR-2 and P-gp, inhibit phosphorylation of VEGFR-2 and downstream PI3K/Akt signaling pathway proteins, induce Apoptosis, block cells in the S phase, inhibit invasive migration, inhibit tubulogenesis in HUVEC cells and inhibit efflux of rhodamine 123 in HeLa/DDP cells. In addition, A20 at 200 mg/kg orally had an acceptable safety profile in acute toxicity assays. The antitumor inhibitory effects on tumor growth in the HeLa/DDP cell xenograft tumor model were 70.9 %, 72.2 %, and 89.5 % at 10, 20 and 40 mg/kg orally. These results suggest that A20 may be a potent VEGFR-2 and P-gp inhibitor with potential for treating cisplatin-resistant cervical Cancer.

Keywords

Cisplatin-resistant cervical cancer; Licochalcone A; P-gp; VEGFR-2; Xenograft tumor.

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