Simvastatin enhances the efficacy of nilotinib in chronic myeloid leukaemia by post-translational modification and drug transporter modulation

Abstract

The resistance of chronic myeloid leukaemia (CML) to tyrosine kinase inhibitors (TKIs) remains a significant clinical problem. Targeting alternative pathways, such as protein prenylation, is known to be effective in overcoming resistance. Simvastatin inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (a key enzyme in isoprenoid-regulation), thereby inhibiting prenylation. We demonstrate that simvastatin alone effectively inhibits proliferation in a panel of TKI-resistant CML cell lines, regardless of mechanism of resistance. We further show that the combination of nilotinib and simvastatin synergistically kills CML cells via an increase in apoptosis and decrease in prosurvival proteins and cellular proliferation. Mechanistically, simvastatin inhibits protein prenylation as shown by increased levels of unprenylated Ras and rescue experiments with mevalonate resulted in abrogation of synergism. The combination also leads to an increase in the intracellular uptake and retention of radiolabelled nilotinib, which further enhances the inhibition of Bcr-Abl kinase activity. In primary CML samples, this combination inhibits clonogenicity in both imatinib-naive and resistant cells. Such combinatorial effects provide the basis for utilising these Food and Drug Administrationapproved drugs as a potential clinical approach in overcoming resistance and improving CML treatment.

Biphasic effects of statins on neuron cell functions under oxygen–glucose deprivation and normal culturing conditions via different mechanisms

“…Statins have been shown to induce cell death via inhibiting prenylation. 23 , 24 Ras activity is known to depend on prenylation. 25 To understand whether the molecular mechanism of pro‐apoptotic effect of statins on neuron cells was associated with its capacity to inhibit prenylation, we examined Ras activity after statins treatment.…”

Effect of Statin Lipophilicity on the Proliferation of Hepatocellular Carcinoma Cells

“…Indeed, the continuous change in the treatment landscape for HCC currently points at a combination of ICIs and tyrosine kinase inhibitors (TKIs) as an effective treatment due to the antiangiogenic and immunomodulatory properties of TKIs [ 50 ]. Several studies have highlighted the beneficial effects of using statins in combination with TKIs, particularly to overcome cases of resistance to TKIs, and, among statins, lipophilic simvastatin appeared to be the most effective in different types of tumors [ 51 , 52 , 53 ]. In our study, simvastatin, but not pravastatin, inhibited the proliferation of HepG2 cells in a dose- and time-dependent manner.…”