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Activation of Nuclear Factor-κB Pathway by Simvastatin and RhoA Silencing Increases Doxorubicin Cytotoxicity in Human Colon Cancer HT29 Cells

Riganti, Chiara, Doublier, Sophie, Costamagna, Costanzo, Aldieri, Elisabetta, Pescarmona, Gianpiero, Ghigo, Dario, Bosia, Amalia·2008·Molecular Pharmacology
DOI 10.1124/mol.108.045286
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Abstract

Doxorubicin efficacy in cancer therapy is hampered by the dose-dependent side effects, which may be overcome by reducing the drug's dose and increasing its efficacy. In the present work, we suggest that the activation of the nuclear factor-kappaB (NF-kappaB) pathway and of nitric-oxide (NO) synthase increases the doxorubicin efficacy in human colon cancer HT29 cells. To induce NF-kappaB, we took into account the effect of doxorubicin itself and of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin; as NF-kappaB inhibitors, we chose the sesquiterpene lactones parthenolide and artemisinin. Simvastatin increased the NF-kappaB activity and NO synthesis, elicited the tyrosine nitration of the multidrug resistance-related protein 3, and enhanced the doxorubicin intracellular accumulation and cytotoxicity. Simvastatin potentiated the effect of doxorubicin on the NF-kappaB pathway and the inducible NO synthase expression. The effects of simvastatin were due to the inhibition of the small G-protein RhoA and of its effector Rho kinase. Parthenolide and artemisinin prevented all of the statin effects by inducing RhoA/Rho kinase activation. On the other hand, they did not reduce the NF-kappaB translocation and doxorubicin intracellular content when RhoA was silenced by small interfering RNA (siRNA). It is interesting that RhoA siRNA was sufficient to increase NF-kappaB translocation, NO synthase activity, doxorubicin accumulation, and cytotoxicity also in non-stimu…

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Research works printed but not linked: 37

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Metadata

Authors
Riganti, C., Doublier, S., Costamagna, C., Aldieri, E., Pescarmona, G., Ghigo, D., & Bosia, A.
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
2008-08
Volume
74
Issue
2
Pages
476-484
ISSN
0026-895X
DOI
10.1124/mol.108.045286
Cited by
58
References
0
Language
en
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