Securin enhances the anti-cancer effects of 6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole (BPR0L075) in human colorectal cancer cells

• Published in: PloS one Vol. 7; no. 4; p. e36006
• Main Authors: Tseng, Ho-Hsing, Chuah, Qiu-Yu, Yang, Pei-Ming, Chen, Chiung-Tong, Chao, Jung-Chi, Lin, Ming-Der, Chiu, Shu-Jun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.04.2012; Public Library of Science (PLoS)
• Subjects: Activation; Androgens; Angiogenesis; Anticancer properties; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Binding sites; Biocompatibility; Biology; Cancer; Cancer therapies; Caspase; Caspases - metabolism; Cdc2 protein; CDC2 Protein Kinase - metabolism; Cell cycle; Cell death; Cell division; Cell proliferation; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA Repair - drug effects; G2 Phase Cell Cycle Checkpoints - drug effects; Gene expression; Genomes; HCT116 Cells; Humans; Indoles; Indoles - pharmacology; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; Life sciences; M Phase Cell Cycle Checkpoints - drug effects; MAP kinase; Medicine; Metastasis; Mortality; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Null cells; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Proteins; Securin; Senescence; Studies; Toxicity; Tumorigenesis; Tumors; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0036006

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.