title: The novel synthetic compound 6-acetyl-9-(3,4,5-trimetho-xybenzyl)-9H-pyrido[2,3-b]indole induces mitotic arrest and apoptosis in human COLO 205 cells.
abstract: A novel synthetic compound 6-acetyl-9-(3,4,5-trimetho-xybenzyl)-9H-pyrido[2,3-b]indole (HAC-Y6) demonstrated selective anticancer activity. In the present study, COLO 205 cells were treated with HAC-Y6 to investigate the molecular mechanisms underlying its effects. HAC-Y6 induced growth inhibition, G2/M arrest and apoptosis in COLO 205 cells with an IC50 of 0.52±0.035 µM. Annexin V/PI double staining demonstrated the presence of apoptotic cells. JC-1 staining analysis showed that HAC-Y6 decreased mitochondrial membrane potential in support of apoptosis. An immunostaining assay revealed that HAC-Y6 depolymerized microtubules. Treatment of COLO 205 cells with HAC-Y6 resulted in increased expression of BubR1 and cyclin B1 and decreased expression of aurora A, phospho-aurora A, aurora B, phospho-aurora B and phospho-H3. HAC-Y6 treatment increased protein levels of active caspase-3, caspase-9, Endo G, AIF, Apaf-1, cytochrome c and Bax, but treatment with the compound caused reduced levels of procaspase-3, procaspase-9, Bcl-xL and Bcl-2. Overall, our results suggest that HAC-Y6 exerts anticancer effects by disrupting microtubule assembly and inducing G2/M arrest, polyploidy and apoptosis via mitochondrial pathways in COLO 205 cells.
authors: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 40402, Taiwan, R.O.C.
authors: Yi-Chien
authors: YC
authors: Lin
authors: Jui-Ying
authors: JY
authors: Tsai
authors: Jai-Sing
authors: JS
authors: Yang
authors: Yueh-Hsuan
authors: YH
authors: Lee
authors: Ernest
authors: E
authors: Hamel
authors: Kuo-Hsiung
authors: KH
authors: Lee
authors: Sheng-Chu
authors: SC
authors: Kuo
authors: Li-Jiau
authors: LJ
authors: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002243:Carbolines / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: C588403:6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido(2,3-b)indole; D002243:Carbolines; D007211:Indoles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D045304:Cytochromes c