Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials

Abstract

Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinase, is classed into three subfamilies based on their structural and activation characteristics: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or non-classic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). PKC inhibitors and activators are used to understand PKC-mediated intracellular signaling pathways and for the diagnosis and treatment of various PKC-associated diseases, such as cancers, neurological diseases, cardiovascular diseases, and infections. Many clinical trials of PKC inhibitors in cancers showed no significant clinical benefits, meaning that there is a limitation to design a cancer therapeutic strategy targeting PKC alone. This review will focus on the activators and inhibitors of PKC and their applications in clinical trials.

Protein Kinase C Inhibitors Reduce SARS-CoV-2 Replication in Cultured Cells

“…To combat RNA viruses with high mutation rates, antiviral drugs targeting host factors might provide better protection than virus-targeted therapeutics, while the administration of host-targeted drugs may cause various side effects. Fortunately, PKC inhibitors have been developed for clinical use and have shown a good safety profile, as PKCs are closely associated with diverse diseases ( 30 ). For example, enzastaurin, a PKC inhibitor intended for the treatment of solid and hematological cancers, has gone through phase III clinical trials.…”

Phosphoregulation of Kinesins Involved in Long-Range Intracellular Transport

“…The nPKC and aPKC isoforms are also activated by tyrosine phosphorylation in the catalytic domain by heterologous enzymes, such as the Src-family kinases and adaptor binding. Distinct PKC isoforms are recruited to the plasma membrane and on the cell's vesicular membrane and act on a specific set of substrates (Geribaldi-Doldán et al, 2019;Kawano et al, 2021).…”

The Effect of A2E on the Ca2+-PKC Signaling Pathway in Human RPE Cells Exposed to Blue Light

“…is protein is water-soluble in its inactive state and free in the cytosol, but it becomes a membrane-bound enzyme after activation [23]. e activation of PKC is lipid-dependent and requires the presence of DAG, as well as an increase in the cytosolic Ca 2+ concentration [24]. When A2E accumulates to a certain extent in the lysosomes of RPE cells, the phototoxicity of A2E increases the permeability of the lysosomal membrane [25], which releases a variety of acidic enzymes into the cytoplasm, inducing reactive oxygen species (ROS) generation and apoptosis [26,27].…”

“…This protein is water-soluble in its inactive state and free in the cytosol, but it becomes a membrane-bound enzyme after activation [ 23 ]. The activation of PKC is lipid-dependent and requires the presence of DAG, as well as an increase in the cytosolic Ca 2+ concentration [ 24 ].…”