Supplementary Figure 1. A drug screen reveals dipyridamole as potentiating the anti-proliferative effects of atorvastatin and fluvastatin. Supplementary Figure 2. Dipyridamole enhances the effects of statin-induced MVA pathway inhibition. Supplementary Figure 3. The relative sensitivity to doxorubicin in 8226DOX and 8226 parental cells is not significantly altered in response to dipyridamole exposure. Supplementary Figure 4. Dipyridamole prevents the statin induced upregulation of HMGCR and HMGCS1. Supplementary Figure 5. Dipyridamole prevents the statin induced upregulation of HMGCR and HMGCS1 through inhibition of SREBP2 cleavage in OCI-AML2 cells. Supplementary Figure 6: Working model of how dipyridamole potentiates the anticancer effects of statins. Supplementary Table 1. Composition of the chemical library.
ARTICLE 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. ©2014 AACR.
