Chimie médicale

Novel Chiral Chalcone Analogs that Induce M Phase Arrest and Apoptosis in HeLa Cells

Abstract

Weiwei Chen, Ruirong Yi, Majid Vahed, Yoshifumi Ohno, Zheng Tian, Shuhan Guo, Xue Ma, Nan Nwe Win, Qisen Li, Ayumu Tsubosaka, Kengo Saito, Shingo Nakamoto, Akiko Suganami, Yutaka Tamura, Takayoshi Arai and Hiroshi Shirasawa

We identified two chiral chalcone analogs CCL360 and CCL361 from the Chiba Chemical Library, which exhibit antiproliferative effects on human cancer cells. Flow cytometry analyses revealed that HeLa and Vero cells treated with CCL360 and CCL361 had higher populations of cells in the G₂/M phase than untreated cells. Docking studies suggested that the R-isomer of CCL361 binds to the taxol binding domain (TBD) of β-tubulin, and the S-isomers of CCL360 and CCL361 bind to β-tubulin at the colchicine binding domain and the TBD. Further investigations using a fluorescent ubiquitination-based cell cycle indicator system revealed that the two compounds caused cell cycle arrest (in the M phase) and apoptosis only in HeLa cells. In non-cancerous Vero cells, however, CCL360 and CCL361 prolonged the G₂/M phase without causing apoptosis. Although increased expression levels of p53 and p21 were observed in all CCL360/361-treated cells, only HeLa cells exhibited increased levels of cleaved poly (ADP-ribose) polymerases and apoptosis. Increases in G₂/M phase populations in CCL360/361-treated cells are likely caused by increases in p-histone H3 (at Ser10) and Cyclin B1 levels. Furthermore, CCL360/361-treated HeLa cells exhibited phosphorylation of p-Plk1 (at Thr210) and dephosphorylation of p-Cdc2 (at Tyr15); these changes were not evident in CCL360/361-treated Vero cells, suggesting that the link between p53 and Plk1 in HeLa cells was likely compromised. Our study indicates that CCL360 and CCL361 are microtubule-targeting agents that can be used as lead compounds for developing novel anticancer drugs.