Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium-dependent activation of HIF-1alpha and P-glyc

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Br J Pharmacol. 2009 Apr;156(7):1054-66. Epub 2009 Mar 9.

Artemisinin
induces doxorubicin resistance in human colon cancer cells via
calcium-dependent activation of HIF-1alpha and P-glycoprotein
overexpression.
 
Riganti C, Doublier S, Viarisio D, Miraglia E, Pescarmona G, Ghigo D, Bosia A.
Department
of Genetics, Biology and Biochemistry, University of Torino, and
Research Center on Experimental Medicine (CeRMS), Via Santena, Torino,
Italy.

BACKGROUND
AND PURPOSE:
Artemisinin is an antimalarial drug exerting pleiotropic
effects, such as the inhibition of the transcription factor nuclear
factor-kappa B and of the sarcoplasmic/endoplasmic reticulum
Ca(++)-ATPase (SERCA) of P. falciparum. As the sesquiterpene lactone
thapsigargin, a known inhibitor of mammalian SERCA, enhances the
expression of P-glycoprotein (Pgp) by increasing the intracellular
Ca(++) ([Ca(++)](i)) level, we investigated whether artemisinin and its
structural homologue parthenolide could inhibit SERCA in human colon
carcinoma HT29 cells and induce a resistance to doxorubicin.

EXPERIMENTAL APPROACH: HT29 cells were incubated with artemisinin or
parthenolide and assessed for SERCA activity, [Ca(++)](i) levels, Pgp
expression, doxorubicin accumulation and toxicity, and translocation of
the hypoxia-inducible factor, HIF-1alpha. KEY RESULTS: Artemisinin and
parthenolide, like the specific SERCA inhibitors thapsigargin and
cyclopiazonic acid, reduced the activity of SERCA. They also increased
intracellular calcium concentration ([Ca(++)](i)) and Pgp expression
and decreased doxorubicin accumulation and cytotoxicity. The
intracellular Ca(++) chelator,
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, and the
inhibitor of calmodulin-dependent kinase II (CaMKII) KN93 prevented
these effects. CaMKII is known to promote the phosphorylation and the
activation of HIF-1alpha, which may induce Pgp. In HT29 cells,
artemisinin and parthenolide induced the phosphorylation of HIF-1alpha,
which was inhibited by KN93.
CONCLUSIONS AND IMPLICATIONS: Our results
suggest that artemisinin and parthenolide may act as SERCA inhibitors
and, like other SERCA inhibitors, induce resistance to doxorubicin in
human colon cancer cells, via the CaMKII-dependent activation of
HIF-1alpha and the induction of Pgp.