International Journal of Cancer. Published Online: 31 Jan 2006. [Link]
Chiara Riganti 1, Sara Orecchia 2, Gianpiero Pescarmona 1, Pier Giacomo Betta 2, Dario Ghigo 1 *, Amalia Bosia 1
1Department of Genetics, Biology and Biochemistry, University of Torino, and Research Center on Experimental Medicine (CeRMS), Torino, Italy
2Pathology Unit, Department of Oncology, Azienda Sanitaria Ospedaliera, Alessandria, Italy
*Correspondence to Dario Ghigo, Dipartimento di Genetica, Biologia e Biochimica – Sezione di Biochimica, Via Santena 5/bis, 10126 Torino, Italy. Email: Dario Ghigo (email@example.com)
Human malignant mesothelioma (HMM) is resistant to many anticancer drugs, including doxorubicin. Mevastatin and simvastatin, 2 inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, potentiated the intracellular accumulation and the cytotoxicity of doxorubicin in HMM cells constitutively expressing P-glycoprotein and multidrug resistance-associated protein 3. This effect of statins was nitric oxide (NO)-dependent, since it was reverted by either an NO synthase inhibitor or an NO scavenging system. The NO synthase up-regulation in HMM and other cells is known to be associated with the activation of the transcription factor NF-B: in HMM cells statins increased the NF-B translocation into the nucleus, decreased the level of the NF-B inhibitor IkB and increased the phosphorylation/activation of IkB kinase (IKK). IKK is under the negative control exerted by RhoA in its prenylated (active) form: incubation of HMM cells with statins lowered the amount of active RhoA and the level of Rho-associated kinase activity. All statins’ effects were reverted by mevalonic acid, thus suggesting that they were mediated by the inhibition of HMGCoA reductase and were likely to be subsequent to the reduced availability of precursor molecules for RhoA prenylation. Both the Rho kinase inhibitor Y27632 and the RhoA inhibitor toxin B (from Clostridium difficile) mimicked the statins’ effects, enhancing doxorubicin accumulation, NO synthesis and IKK phosphorylation and decreasing the amount of IkB in HMM cells. Simvastatin, Y27632 and toxin B elicited tyrosine nitration in the P-glycoprotein, thus providing a likely mechanism by which NO reverts the doxorubicin resistance in HMM cells.