Arsenic trioxide causes redistribution of cell cycle, caspase activation, and GADD expression in human colonic, breast, and pancreatic cancer cells

Xinquan Li, Xianzhong Ding, Thomas E. Adrian

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

Arsenic trioxide is valuable for treatment of promyelocytic leukemia, but less attention has been paid to its therapeutic potential for other cancers. In this study, the effects of arsenic trioxide were tested in human pancreatic (AsPC-1), colonic (HT-29), and breast (MCF-7) cancer cells. In all three cancer cell lines, arsenic trioxide inhibited proliferation in a concentration and time-dependent manner, as measured by 3H-methyl thymidine incorporation and cell counting. Coincident with inhibition of growth, arsenic trioxide induced marked morphologic changes, including reduced cytoplasmic volume, membrane blebbing, and nuclear condensation consistent with apoptosis. Propidium iodide DNA staining at 24 hours revealed cell cycle arrest in the G0/G1 phase and an increase in the S phase, while at 72 hr there was G2/M phase arrest with a marked increase in the sub-G0/G1, apoptotic cell population. The DNA fragmentation induced by arsenic trioxide was confirmed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay in all cell lines. Western blot analysis revealed activation of caspase -3, -7, and -9 by arsenic trioxide. Caspase-3 activity was confirmed by demonstrating cleavage of its downstream target, poly ADP-ribose polymerase (PARP). Expression of the antiapoptosis protein, Bcl-2, was time-dependently decreased. In contrast, arsenic trioxide markedly enhanced the expression of the p21 protein, GADD45 and GADD153, in a time-dependent manner. These findings suggest that arsenic trioxide has potential as a therapeutic agent for these cancers.

Original languageEnglish
Pages (from-to)389-400
Number of pages12
JournalCancer Investigation
Volume22
Issue number3
DOIs
Publication statusPublished - 2004
Externally publishedYes

Keywords

  • Arsenic trioxide
  • Breast
  • Cancer
  • Colon
  • Pancreas

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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