title: New benzimidazole acridine derivative induces human colon cancer cell apoptosis in vitro via the ROS-JNK signaling pathway.
abstract: OBJECTIVE
  To investigate the mechanisms underlying anticancer action of the benzimidazole acridine derivative N-{(1H-benzo[d]imidazol-2-yl)methyl}-2-butylacridin-9-amine(8m) against human colon cancer cells in vitro.
  
  
  METHODS
  Human colon cancer cell lines SW480 and HCT116 were incubated in the presence of 8m, and then the cell proliferation and apoptosis were measured. The expression of apoptotic/signaling genes and proteins was detected using RT-PCR and Western blotting. ROS generation and mitochondrial membrane depolarization were visualized with fluorescence microscopy.
  
  
  RESULTS
  8m dose-dependently suppressed the proliferation of SW480 and HCT116 cells with IC50 values of 6.77 and 3.33 μmol/L, respectively. 8m induced apoptosis of HCT116 cells, accompanied by down-regulation of Bcl-2, up-regulation of death receptor-5 (DR5), truncation of Bid, cleavage of PARP, and activation of caspases (including caspase-8 and caspase-9 as well as the downstream caspases-3 and caspase-7). Moreover, 8m selectively activated JNK and p38 without affecting ERK in HCT116 cells. Knockout of JNK1, but not p38, attenuated 8m-induced apoptosis. In addition, 8m induced ROS production and mitochondrial membrane depolarization in HCT116 cells. Pretreatment with the antioxidants N-acetyl cysteine or glutathione attenuated 8m-induced apoptosis and JNK activation in HCT116 cells.
  
  
  CONCLUSIONS
  The new benzimidazole acridine derivative, 8m exerts anticancer activity against human colon cancer cells in vitro by inducing both intrinsic and extrinsic apoptosis pathways via the ROS-JNK1 pathway.
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, China.|The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, China.|The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Bi-zhu
authors.initials: BZ
authors.lastname: Chu
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|Shenzhen Anti-Tumor Drug Development Engineering Laboratory, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, China.|The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|Shenzhen Anti-Tumor Drug Development Engineering Laboratory, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Chun-mei
authors.initials: CM
authors.lastname: Gao
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Lu-lu
authors.initials: LL
authors.lastname: Li
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Qin-sheng
authors.initials: QS
authors.lastname: Sun
authors.affiliation: Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China.
authors.forename: Zhi-fa
authors.initials: ZF
authors.lastname: Shen
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|Shenzhen Anti-Tumor Drug Development Engineering Laboratory, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yu-yang
authors.initials: YY
authors.lastname: Jiang
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases