BPR0L075 [6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-
indole] is a novel anti-microtubule
drug with anti-
tumor and anti-angiogenic activities in vitro and in vivo.
Securin is required for
genome stability, and is expressed abundantly in most
cancer cells, promoting cell proliferation and
tumorigenesis. In this study, we found that
BPR0L075 efficiently induced cell death of HCT116 human
colorectal cancer cells that have higher expression levels of
securin. The cytotoxicity of
BPR0L075 was attenuated in isogenic
securin-null HCT116 cells.
BPR0L075 induced DNA damage response, G(2)/M arrest, and activation of the spindle assembly checkpoint in HCT116 cells. Interestingly,
BPR0L075 induced phosphorylation of
securin.
BPR0L075 withdrawal resulted in degradation of
securin, mitotic exit, and mitotic catastrophe, which were attenuated in
securin-null cells. Inhibition of cdc2 decreased
securin phosphorylation, G(2)/M arrest and cell death induced by
BPR0L075. Moreover,
BPR0L075 caused cell death through a
caspase-independent mechanism and activation of JNK and
p38 MAPK pathways. These findings provided evidence for the first time that
BPR0L075 treatment is beneficial for the treatment of human
colorectal tumors with higher levels of
securin. Thus, we suggest that the expression levels of
securin may be a predictive factor for application in anti-
cancer therapy with
BPR0L075 in human
cancer cells.