Anti-cancer mechanisms of PDE5 inhibitors

Anti-cancer mechanisms of PDE5 inhibitors. Via activation of the cGMP/PKG signaling cascade, PDE5-Is can induce apoptosis in cancer cells via various pathways; activation of c-Jun NH2-terminal kinase (JNK) via phosphorylation of mitogen-activated protein kinase kinase kinase 1 (MEKK1), phosphorylation of β-catenin and inducing its proteosomal degradation which leads to decreased expression of Wnt/β-catenin regulated proteins, such as cyclin D1 and survivin in addition to blocking the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathways. PDE5-Is could also increase intracellular levels of other chemotherapeutic agents via inhibition of the ATP-binding cassette (ABC) transporter-mediated drug efflux, averting multidrug resistance (MDR) in addition to increasing cellular drug uptake via enhancing endocytosis. Moreover, PDE5-Is synergize with other chemotherapeutic agents via boosting various apoptotic, autophagy, mitotic arrest and chaperone degradation pathways. PDE5-Is can also abrogate the function of myeloid-derived suppressor cells (MDSCs) via suppression of arginase-1 (Arg-1) and nitric oxide synthase–2 (NOS-2) production. This results in enhanced intratumoral T-cell infiltration and activation and restores both systemic and tumor-specific immunity. P = phosphorylation.

Publication

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives (2023) Ahmed K. ElHady, et al. Pharmaceuticals (Basel). 2023 Sep;16(9):1266. Figure: F3. Homo sapiens

Disease mentions