title: Derivatives containing both coumarin and benzimidazole potently induce caspase-dependent apoptosis of cancer cells through inhibition of PI3K-AKT-mTOR signaling.
abstract: Coumarins are a large family of compounds derived from a wide range of plants, fungi, and bacteria, and coumarin derivatives can have extremely variable structures and consequently diverse biological properties including antitumor activity. Compounds that bear a benzimidazole moiety are known to possess antitumor activity and a variety of other biological activities. High-throughput screening of a compound library identified a coumarin-containing and a benzimidazole-containing compound [#32, 7-(diethylamino)-3-(1-methyl-1H-benzimidazol-2-yl)-2H-chromen-2-one] that has potent anticancer activity. Evaluation of 17 additional analogs further identified three compounds with anticancer activity in 14 different human cancer cell lines. Fluorescence-activated cell sorting and western blotting analyses suggested that these compounds can induce caspase-dependent apoptosis. Real-time reverse transcriptase PCR analyses of 26 cancer-related genes revealed that seven genes (NPPB, ATF3, DDIT4, CDH10, TSPAN14, TXNIP, and AXL) were significantly upregulated and nine genes (PAGE4, LRP8, SNCAIP, IGFBP5, SLCO2A1, CLDN2, ESRRG, D2HGDH, and PDGFRA) were significantly downregulated. The most upregulated gene is natriuretic peptide precursor B (NPPB) or brain natriuretic peptide, which is increased by 7-, 27-, and 197-fold at 12, 24, and 48 h, respectively. The second most upregulated gene is ATF3, which is increased by 23-fold at the 48 h timepoint. PAGE4 and IGFBP5 are the two most downregulated genes, with a 17-fold reduction in both genes. The expression of several genes (DDIT4, PDGFRA, LRP8, IGFBP5) and western blotting data on key signaling proteins indicate that compound #32 significantly inhibits the PI3K-AKT-mTOR pathway, an intracellular signaling pathway critical in cell proliferation and apoptosis.
authors: aCenter for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA bInstitute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, China.
authors: Haitao
authors: H
authors: Liu
authors: Yubin
authors: Y
authors: Wang
authors: Ashok
authors: A
authors: Sharma
authors: Rui
authors: R
authors: Mao
authors: Na
authors: N
authors: Jiang
authors: Boying
authors: B
authors: Dun
authors: Jin-Xiong
authors: JX
authors: She
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D062126:Databases, Chemical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D020169:Caspases; D003374:Coumarins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases