Derivatives containing both coumarin and benzimidazole potently induce caspase-dependent apoptosis of cancer cells through inhibition of PI3K-AKT-mTOR signaling

Haitao Liu, Yubin Wang, Ashok Kumar Sharma, Rui Mao, Na Jiang, Boying Dun, Jin-Xiong She

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)667-677
Number of pages11
JournalAnti-Cancer Drugs
Volume26
Issue number6
DOIs
StatePublished - Jun 9 2015

Fingerprint

Caspases
Phosphatidylinositol 3-Kinases
Apoptosis
Genes
Coumarins
Neoplasms
Natriuretic Peptides
Down-Regulation
Western Blotting
Critical Pathways
Brain Natriuretic Peptide
Neoplasm Genes
Reverse Transcriptase Polymerase Chain Reaction
Libraries
coumarin
benzimidazole
Real-Time Polymerase Chain Reaction
Flow Cytometry
Fungi
Cell Proliferation

Keywords

  • apoptosis
  • benzimidazole
  • coumarin
  • drug discovery
  • gene expression

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research
  • Oncology

Cite this

Derivatives containing both coumarin and benzimidazole potently induce caspase-dependent apoptosis of cancer cells through inhibition of PI3K-AKT-mTOR signaling. / Liu, Haitao; Wang, Yubin; Sharma, Ashok Kumar; Mao, Rui; Jiang, Na; Dun, Boying; She, Jin-Xiong.

In: Anti-Cancer Drugs, Vol. 26, No. 6, 09.06.2015, p. 667-677.

Research output: Contribution to journalArticle

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