A novel bis-benzylidenecyclopentanone derivative, BPR0Y007, inducing a rapid caspase activation involving upregulation of Fas (CD95/APO-1) and wild-type p53 in human oral epidermoid carcinoma cells

Shin Hun Juang, Wen Yu Pan, Ching Chuan Kuo, Jing Ping Liou, Yi Mei Hung, Li Tzong Chen, Hsing Pang Hsieh, Jang Yang Chang

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

BPR0Y007, a bis-benzylidenecyclopentanone derivative (2,5-bis- (4-hydroxy-3-methoxybenzylidene) cyclopentanone), was identified in our laboratory as a novel antineoplastic agent with a broad spectrum of antitumor activity against many human cancer cells. A previous study showed that BPR0Y007 inhibited DNA topoisomerase I (Top 1) activity and prevented tubulin polymerization. Notably, no cross-resistance with BPR0Y007 was observed in camptothecin-, VP-16- or vincristine-resistant cell lines. In this study, we further investigated the cellular and molecular events underlying the antitumoral function of this compound in human oral epidermoid carcinoma KB cells, focusing on the early cytotoxic effect. Treatment of KB cells with BPR0Y007-induced G2/M phase arrest followed by sub-G1 phase accumulation. Annexin-V-propidium iodide (PI) binding assay and DNA fragmentation assay further indicated that BPR0Y007-induced cell death proceeded through an apoptotic pathway as opposed to via necrosis. This compound produced a time-dependent activation of caspases-3 and -8, however, another caspase-3 initiator, caspase-9, was only marginally activated at later time point. We further demonstrated that the activation of the caspases cascade and nuclear fragmentation was not associated with inactivated Bcl-2 and perturbed mitochondrial membrane potential by BPR0Y007. The finding that BPR0Y007-induced apoptosis through a membrane-mediated mechanism was supported by up-regulated expression of Fas (CD95/APO-1), but not Fas-L. Furthermore, up-regulation of p53 and its affected gene, MDM2, in KB cells was found after BPR0Y007 exposure. Overall, our results demonstrated that the BPR0Y007 could induce an early cytotoxic apoptosis through a caspase-8-dependent but mitochondrial-caspase-9 independent pathway, and involving upregulation of p53.

Original languageEnglish
Pages (from-to)293-303
Number of pages11
JournalBiochemical Pharmacology
Volume68
Issue number2
DOIs
Publication statusPublished - Jul 15 2004

Keywords

  • 2,5-bis-(4-hydroxy-3-methoxybenzylidene) cyclopentanone
  • 3,3′-Dihexyloxacarbocyanine iodide
  • BPR0Y007
  • DiOC (3)
  • DNA topoisomerase I
  • mitochondrial potential transition
  • MPT
  • PBS
  • phosphate buffered saline
  • PI
  • propidium iodide
  • Top 1

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'A novel bis-benzylidenecyclopentanone derivative, BPR0Y007, inducing a rapid caspase activation involving upregulation of Fas (CD95/APO-1) and wild-type p53 in human oral epidermoid carcinoma cells'. Together they form a unique fingerprint.

Cite this