Statins revert doxorubicin resistance via nitric oxide in malignant mesothelioma

Abstract

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 Pglycoprotein 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-jB: in HMM cells statins increased the NF-jB translocation into the nucleus, decreased the level of the NF-jB inhibitor IkBa and increased the phosphorylation/activation of IkB kinase a (IKKa). IKKa 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 IKKa phosphorylation and decreasing the amount of IkBa 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. ' 2006 Wiley-Liss, Inc.

Lovastatin enhances the antitumoral and apoptotic activity of doxorubicin in murine tumor models

“…These results are in agreement with those obtained by Feleszko et al (27) in sarcoma, colon and lung carcinoma tumor-models. The combination of LOV with cisplatin (23), sulindac (28) (30). Contrasting with the results mentioned above, Bardeleben et al (31) working with CHO-K1, HepG2 and Jurkat cells, found that pretreatment with LOV rendered them resistant to DOX.…”

RhoA Silencing Reverts the Resistance to Doxorubicin in Human Colon Cancer Cells

“…In human mesothelioma cells, which similarly overexpress both Pgp and MRP3 and are constitutively resistant to doxorubicin, we have previously corrected the resistance to doxorubicin by inducing NF-nB activation and NO synthesis with statins (6): we have found that statins lower the amount of active RhoA and the level of Rho-associated kinase activity. Indeed, both the Rho kinase inhibitor Y27632 and the RhoA inhibitor toxin B mimic the effects of the statins and are able to induce NF-nB and NO synthesis and to revert the resistance to doxorubicin (6).…”

“…A relationship between Rho kinase and InB kinase (IKK) a/InBa/nuclear factor-nB (NF-nB) pathway has been hypothesized in other cell types (6,10,11). Therefore, we investigated whether RhoA inhibition in HT29 cells may lead to an IKKmediated nuclear translocation of NF-nB.…”

“…Thus, the modulation of these Rho-driven mechanisms may influence therapeutic efficacy and/ or side effects of conventional antineoplastic therapy. We have previously shown that statins can revert doxorubicin resistance in malignant mesothelioma cells (6). Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the enzyme catalyzing the rate-limiting step in cholesterol synthesis.…”

“…We have reported that the statin-induced reversion of doxorubicin resistance is associated with a decrease of the amount of active RhoA and of the level of Rho-associated kinase activity. Indeed, mevalonate reverted the effect of statins, whereas the Rho kinase inhibitor Y27632 and the RhoA inhibitor toxin B mimicked the effects of statins on doxorubicin resistance (6). Experimental approaches to inhibit Rho have focused on the attenuation of their COOH-terminal isoprenylation (5).…”