Abstract
Angelicin, which is categorized into the class of angular furanocoumarin, has been indicated as a potential compound that has multiple activities in various pharmacological substances, including anticonvulsants, intercalating agents, and tranquilizing agents. Recently, a series of novel angelicin derivatives have been synthesized by our drug discovery team. Preliminary screens indicated that many of them have potent anti-tumor proliferative effect. Among them, 8-Benzoyl-4-methyl-9-phenyl- 2H-furo[2,3-h]chromen-2-one (BPR2P0001S0) is the most potent anti-cancer agent against various human cancer cells growth. However, the mechanism of action underlying this anti-cancer effect is not fully understood. In the present study, we demonstrated that BPR2P0001S0 exerted potent anti-proliferation activity against several squamous cell carcinoma cell lines, such as KB and Ca-9-22, with IC50 values in the nanomolar range. Nevertheless, this compound was less potent on the inhibition of adenocarcinoma cell lines. No growth inhibitory effect was observed in normal cells, such as human umbilical vein endothelial cells (HUVEC) and fibroblast Detroit551. In the present study, we chose KB cell as the experimental model for further research. Clonogenic assay supported that BPR2P0001S0 treatment significantly reduce the proliferative capacity of KB cells, but did not cause cell death. Further studies showed that BPR2P0001S0 was able to induce DNA damage, senescence and cell cycle arrest in S phase. In addition, this compound could also cause changes in glucose metabolism by down-regulation of the expression level of c-Myc, hexokinase II and lactate dehydrogenase A mRNA and protein in KB cells. Moreover, cell growth inhibition induced by BPR2P0001S0 could be rescued by addition of lactate and methyl pyruvate in KB cells. Preclinical animal study demonstrated that BPR2P0001S0 exhibited anti-tumor activity against the growth of KB xenograft tumor in NOD/SCID mice. Overall, based on our results, we concluded that BPR2P0001S0 causes cancer growth inhibition, DNA damage, S phase arrest, cell senescence and cancer metabolism alteration. Although network that connects with each effect is under investigation, we can deduce that BPR2P0001S0 has potential to be a new therapeutic agent toward human squamous cell carcinoma growth.