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Docetaxel as a Model Compound to Promote HDL (High-Density Lipoprotein) Biogenesis and Reduce Atherosclerosis

Journal

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 43, Issue 5, Pages 609-617

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.122.318275

Keywords

atherosclerosis; cholesterol; desmocollin 1; docetaxel; high-density lipoprotein

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The identification of DSC1 as a negative regulator of HDL biogenesis has led to a reconsideration of the hypothesis that HDL biogenesis reduces atherosclerosis. DSC1, which can be targeted by the drug docetaxel, has shown to promote HDL biogenesis and inhibit atherogenic proliferation of vascular smooth muscle cells. Animal studies have demonstrated that docetaxel reduces dyslipidemia-induced atherosclerosis, highlighting the importance of DSC1 as a potential target for HDL biogenesis.
The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to revisit the old HDL biogenesis hypothesis: HDL biogenesis reduces atherosclerosis. The location and function of DSC1 suggest that DSC1 is a druggable target for the promotion of HDL biogenesis, and the discovery of docetaxel as a potent inhibitor of the DSC1 sequestration of apolipoprotein A-I has provided us with new opportunities to test this hypothesis. The FDA-approved chemotherapy drug docetaxel promotes HDL biogenesis at low-nanomolar concentrations that are far lower than used in chemotherapy. Docetaxel has also been shown to inhibit atherogenic proliferation of vascular smooth muscle cells. In accordance with these atheroprotective effects of docetaxel, animal studies have shown that docetaxel reduces dyslipidemia-induced atherosclerosis. In the absence of HDL-directed therapies for atherosclerosis, DSC1 constitutes an important new target for the promotion of HDL biogenesis, and the DSC1-targeting compound docetaxel serves as a model compound to prove the hypothesis. In this brief review, we discuss opportunities, challenges, and future directions for using docetaxel in the prevention and treatment of atherosclerosis.

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