Investigational New Drugs

, Volume 29, Issue 6, pp 1276–1283 | Cite as

The anti-cancer activity of dihydroartemisinin is associated with induction of iron-dependent endoplasmic reticulum stress in colorectal carcinoma HCT116 cells

PRECLINICAL STUDIES

Summary

Dihydroartemisinin (DHA), the main active metabolite of artemisinin derivatives, is among the artemisinin derivatives possessing potent anti-malarial and anti-cancer activities. In the present study, we found that DHA displayed significant anti-proliferative activity in human colorectal carcinoma HCT116 cells, which may be attributed to its induction of G1 phase arrest and apoptosis. To further elucidate the mechanism of action of DHA, a proteomic study employed two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was performed. Glucose-regulated protein 78 (GRP78), which is related with endoplasmic reticulum stress (ER stress), was identified to be significantly up-regulated after DHA treatment. Further study demonstrated that DHA enhanced expression of GRP78 as well as growth arrest and DNA-damage-inducible gene 153 (GADD153, another ER stress-associated molecule) at both mRNA and protein levels. DHA treatment also led to accumulation of GADD153 in cell nucleus. Moreover, pretreatment of HCT116 cells with the iron chelator deferoxamine mesylate salt (DFO) abrogated induction of GRP78 and GADD153 upon DHA treatment, indicating iron is required for DHA-induced ER stress. This result is consistent with the fact that the anti-proliferative activity of DHA is also mediated by iron. We thus suggest the unbalance of redox may result in DHA-induced ER stress, which may contribute, at least in part, to its anti-cancer activity.

Keywords

Dihydroartemisinin 2-DE ER stress GRP78 GADD153 

Abbreviations

ARTs

Artemisinin and its derivatives

2-DE

Two-dimensional gel electrophoresis

DFO

Deferoxamine mesylate salt

DHA

Dihydroartemisinin

ER

Endoplasmic reticulum

GADD153

Growth arrest and DNA-damage-inducible gene 153

GRP78

Glucose-regulated protein 78

HSPs

Heat-shock proteins

IEF

Isoelectric focusing

MALDI-TOF MS

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

PI

Propidium iodide

SRB

Sulforhodamine B

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiPeople’s Republic of China

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