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.

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.