5 Citations (Scopus)

Abstract

Here, we present evidence of a novel microtubule-disrupting agent, N-deacetyl-N-(chromone-2-carbonyl)-thiocolchicine (TCD), exhibiting potent antitumor activity (with IC50 values in the nanomolar range) against hepatocellular carcinoma cell lines. Cell cycle analysis revealed that TCD induced G2/M cell-cycle arrest in a dose- and time-dependent manner in both Hep-J5 and Mahlavu HCC cell lines. TCD also induced a decrease in mitochondrial membrane potential (Δψm) and caused DNA damage. Mechanistically, TCD activated protein kinase RNA-like endoplasmic reticular kinase and several transcription factors, including activating transcription factor (ATF) 6, ATF4, ATF3, and the CCAAT-enhancer binding protein homologous protein. These data clearly demonstrate that the antitumor activity of TCD is mechanistically linked to its capacity to trigger both intrinsic and extrinsic apoptotic cell death via endoplasmic reticular stress pathway. The potent antitumor activity of TCD was similarly demonstrated in a hepatocellular carcinoma xenograft model, where 5 and 10 mg/kg doses of TCD significantly arrested Hep-J5 and Mahlavu tumor growth. Our finding suggests that TCD is a promising therapeutic agent against hepatocellular carcinoma; further translational assessment of its clinical usage is warranted.

Original languageEnglish
Article numbere0136340
JournalPLoS One
Volume10
Issue number9
DOIs
Publication statusPublished - Sep 10 2015

Fingerprint

Cell death
hepatoma
Microtubules
microtubules
cell death
Hepatocellular Carcinoma
Cell Death
Cells
Activating Transcription Factor 6
transcription factors
Chromones
cell lines
G2 Phase Cell Cycle Checkpoints
eIF-2 Kinase
CCAAT-Enhancer-Binding Proteins
Cell Line
Mitochondrial Membrane Potential
cells
dosage
membrane potential

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A novel microtubule-disrupting agent induces endoplasmic reticular stress-mediated cell death in human hepatocellular carcinoma cells. / Ho, Chun Te; Chang, Yu Jia; Yang, Li Xi; Wei, Po Li; Liu, Tsan Zon; Liu, Jun Jen.

In: PLoS One, Vol. 10, No. 9, e0136340, 10.09.2015.

Research output: Contribution to journalArticle

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AU - Chang, Yu Jia

AU - Yang, Li Xi

AU - Wei, Po Li

AU - Liu, Tsan Zon

AU - Liu, Jun Jen

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