Immediate Utility of Two Approved Agents to Target Both the Metabolic Mevalonate Pathway and Its Restorative Feedback Loop

Abstract

New therapies are urgently needed for hematologic malignancies, especially in patients with relapsed acute myelogenous leukemia (AML) and multiple myeloma. We and others have previously shown that FDA-approved statins, which are used to control hypercholesterolemia and target the mevalonate pathway (MVA), can trigger tumor-selective apoptosis. Our goal was to identify other FDA-approved drugs that synergize with statins to further enhance the anticancer activity of statins in vivo. Using a screen composed of other FDA approved drugs, we identified dipyridamole, used for the prevention of cerebral ischemia, as a potentiator of statin anticancer activity. The statin-dipyridamole combination was synergistic and induced apoptosis in multiple myeloma and AML cell lines and primary patient samples, whereas normal peripheral blood mononuclear cells were not affected. This novel combination also decreased tumor growth in vivo. Statins block HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the MVA pathway. Dipyridamole blunted the feedback response, which upregulates HMGCR and HMG-CoA synthase 1 (HMGCS1) following statin treatment. We further show that dipyridamole inhibited the cleavage of the transcription factor required for this feedback regulation, sterol regulatory element-binding transcription factor 2 (SREBF2, SREBP2). Simultaneously targeting the MVA pathway and its restorative feedback loop is preclinically effective against hematologic malignancies. This work provides strong evidence for the immediate evaluation of this novel combination of FDA-approved drugs in clinical trials. Cancer Res; 74(17); 4772-82. Ó2014 AACR.

Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study

“…4 Farnesyl diphosphate, geranylgeranyl diphosphate isoprenylate, and small GTPases such as Ras and Rho are involved in tumorigenesis and cancer cell survival. 30,31 In addition, statins also ameliorated hepatic steatosis and inflammation, which were strongly associated with DM and liver disease, related to the development of HCC. [32][33][34] However, how statins have protective effects in patients with DM or liver disease is poorly understood.…”

Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design

“…3B) [as reported for statins (63)] because several cell cycles are necessary to exhaust the endogenous reserve of cholesterol. The effectiveness of VFV against cancer cells is already within the range of cellular potencies of statins [e.g., (33,47,63)] and approaching a mean concentration reported for clinical anticancer drugs (1-10 M) (64). Thus, these results serve as an initial proof of concept, encouraging searches for stronger human CYP51 inhibitors.…”

“…However, by blocking an early step in the pathway, statins affect not only production of cholesterol but also the formation of other physiologically important compounds [e.g., ubiquinone, dolichols, prenylated proteins (33)], and therefore, in long-term use, can cause dose-dependent side effects [mainly myopathy (34)(35)(36)(37)] leading to discontinuation of treatment in up to 20% of patients (38,39). Also, because, due to uptake transporters, statins generally target the liver (where 70% of cholesterol is synthesized), in clinical trials for cancer they have to be used at much higher doses (33) to reach other organs and tissues. Accordingly, although sometimes supplemented with intermediates [e.g., ubiquinone (17)], they produce stronger side effects.…”

The interplay between cell signalling and the mevalonate pathway in cancer

“…Most small GTPases, like RAS and RHO, are isoprenylated 49 , and many are involved in tumourigenesis. Inhibiting the MVA pathway can reduce the isoprenylation of RAS, RHO and other small GTPases [50][51][52] , and leads to cell death in some cancer cells. This cell death can be reversed by the addition of GGPP, and sometimes FPP, suggesting that these MVA pathway metabolites are essential for tumour cell viability [52][53][54][55][56] .…”