Abstract
Aplysiatoxin (ATX) is a protein kinase C (PKC) activator with potent tumor-promoting activity. In contrast, 10-methyl-aplog-1 (1), a simplified analog of ATX, was anti-proliferative towards several cancer cell lines without significant tumor-promoting and proinflammatory activities. To determine the effects of the phenolic group on the biological activities of 1, we synthesized new derivatives (2, 3) that lack the phenolic hydroxyl group and/or the aromatic ring. Compound 2, like 1, showed potent anti-proliferative activity against several cancer cell lines, but little with respect to tumor-promoting and proinflammatory activities. In contrast, 3 exhibited weaker growth inhibitory activity, and promoted inflammation and tumorigenesis. The binding affinity of 3 for PKCδ, which is involved in growth inhibition and apoptosis, was several times lower than those of 1 and 2, possibly due to the absence of the hydrogen bond and CH/π interaction between its side chain and either Met-239 or Pro-241 in the PKCδ-C1B domain. These results suggest that both the aromatic ring and phenolic hydroxyl group can suppress the proinflammatory and tumor-promoting activities of 1 and, therefore, at least the aromatic ring in the side chain of 1 is indispensable for developing anti-cancer leads with potent anti-proliferative activity and limited side effects. In accordance with the binding affinity, the concentration of 3 necessary to induce PKCδ-GFP translocation to the plasma membrane and perinuclear regions in HEK293 cells was higher than that of 1 and 2. However, the translocation profiles for PKCδ-GFP due to induction by 1–3 were similar.
Highlights
Naturally-occurring tumor-promoters such as phorbol esters, ingenol esters, teleocidins, and aplysiatoxins, exhibit potent tumor-promoting and proinflammatory activities [1], and show anti-proliferative and proapoptotic activities towards several cancer cell lines [2,3]
Tumor promoters bind to C1 domains (C1A and C1B) of conventional protein kinase C (PKC) (α, βI, βII, γ) and novel
PKC activation has been considered a potential strategy for cancer therapy [7], of these compounds are protein (PKC)isisozymes, a family by of serine/threonine kinaseseffects, involvedsuch as the application of PKC ligands to kinase clinicalC uses strictly limited their severe adverse in cellular signal transductions related to proliferation, differentiation, and apoptosis [4,5]
Summary
Naturally-occurring tumor-promoters such as phorbol esters, ingenol esters, teleocidins, and aplysiatoxins, exhibit potent tumor-promoting and proinflammatory activities [1], and show anti-proliferative and proapoptotic activities towards several cancer cell lines [2,3]. Molecules 2017, 22, 631 targets of these compounds are protein kinase C (PKC) isozymes, a family of serine/threonine kinases involved in cellular signal transductions related to proliferation, differentiation, and apoptosis [4,5]. PKC (δ, Σ, η,2017, θ) isozymes, and recruit them from the cytoplasm to the cell membrane to activate the Molecules. PKC activation has been considered a potential strategy for cancer therapy [7], of these compounds are protein (PKC)isisozymes, a family by of serine/threonine kinaseseffects, involvedsuch as the application of PKC ligands to kinase clinicalC uses strictly limited their severe adverse in cellular signal transductions related to proliferation, differentiation, and apoptosis [4,5]. The representative η, θ) isozymes, and recruit them from the cytoplasm to the cell membrane to activate the enzymes [6]
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