Cyclic AMP‐hydrolyzing phosphodiesterase inhibitors potentiate statin‐induced cancer cell death. Issue 10 (25th August 2020)

• Record Type: Journal Article
• Authors: Longo, Joseph; Pandyra, Aleksandra A.; Stachura, Paweł; Minden, Mark D.; Schimmer, Aaron D.; Penn, Linda Z.
• Is Part Of: Molecular oncology. Volume 14:Issue 10(2020)
• Page Start: 2533
• Page End: 2545
• Publication Date: 2020-08-25
• Subjects: cilostazol -- dipyridamole -- mevalonate pathway -- phosphodiesterase inhibitor -- SREBP2 -- statins; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12775
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Dipyridamole, an antiplatelet drug, has been shown to synergize with statins to induce cancer cell‐specific apoptosis. However, given the polypharmacology of dipyridamole, the mechanism by which it potentiates statin‐induced apoptosis remains unclear. Here, we applied a pharmacological approach to identify the activity of dipyridamole specific to its synergistic anticancer interaction with statins. We evaluated compounds that phenocopy the individual activities of dipyridamole and assessed whether they could potentiate statin‐induced cell death. Notably, we identified that a phosphodiesterase (PDE) inhibitor, cilostazol, and other compounds that increase intracellular cyclic adenosine monophosphate (cAMP) levels potentiate statin‐induced apoptosis in acute myeloid leukemia and multiple myeloma cells. Additionally, we demonstrated that both dipyridamole and cilostazol further inhibit statin‐induced activation of sterol regulatory element‐binding protein 2, a known modulator of statin sensitivity, in a cAMP‐independent manner. Taken together, our data support that PDE inhibitors such as dipyridamole and cilostazol can potentiate statin‐induced apoptosis via a dual mechanism. Given that several PDE inhibitors are clinically approved for various indications, they are immediately available for testing in combination with statins for the treatment of hematological malignancies. Abstract : Dipyridamole, an antiplatelet drug, synergizes with statins to induce tumor‐specific apoptosis. Here, we took a pharmacological approach to dissect the mechanism of action. By evaluating compounds that phenocopy the individual activities of dipyridamole, we uncovered that cAMP‐hydrolyzing phosphodiesterase inhibitors can potentiate statin‐induced apoptosis via a dual mechanism. This approach may be useful when interrogating novel functions of other repurposed drugs.