The effect of high dose Cilostazol and Rosuvastatin on myocardial damage in patients with elective percutaneous coronary intervention (PREVENT trial)

Arı, Hasan; Emlek, Nadir; Coşar, Selvi; Aydın, Cihan; Doganay, K.; Karakuş, Alper; Zengin, İsmet; Bozat, Tahsin; Melek, Mehmet

doi:10.1093/eurheartj/eht307.p680

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“…Given that a number of PDE inhibitors are poised for repurposing and that statins have demonstrated anticancer activity in early-phase clinical trials [42][43][44][45][46][47][48][49], further studies are needed to evaluate the therapeutic benefit of a statin-PDE inhibitor combination for the treatment of cancer. As the combination of cilostazol and statins has already been evaluated clinically in healthy subjects [50,51] and in patients with cardiovascular indications [52,53] without added adverse effects, there is the possibility of fast-tracking these agents to phase II trials in AML and MM.…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP‐hydrolyzing phosphodiesterase inhibitors potentiate statin‐induced cancer cell death

et al. 2020

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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 statininduced 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.

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