Derivatives containing both coumarin and benzimidazole potently induce caspase-dependent apoptosis of cancer cells through inhibition of PI3K-AKT-mTOR signaling. Issue 6 (July 2015)

• Record Type: Journal Article
• Authors: Liu, Haitao; Wang, Yubin; Sharma, Ashok; Mao, Rui; Jiang, Na; Dun, Boying; She, Jin-Xiong
• Is Part Of: Anti-cancer drugs. Volume 26:Issue 6(2015)
• Publication Date: 2015-07
• Subjects: apoptosis -- benzimidazole -- coumarin -- drug discovery -- gene expression; Antineoplastic agents -- Periodicals; Cancer -- Chemotherapy -- Periodicals; Antineoplastic Agents -- therapeutic use -- Periodicals; Drug Therapy -- Periodicals; 616.994061
• DOI: 10.1097/CAD.0000000000000232
• Languages: English
• ISSNs: 0959-4973

Abstract

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.