In vivo anti-cancer activity of 10-methyl-aplog-1, a simplified analog of aplysiatoxin, and its possible signaling pathway associated with G1 arrest

Naturally occurring protein kinase C (PKC) activators such as phorbol esters, teleocidins, and aplysia-toxins, have the potential to become anti-cancer agents, since they are anti-proliferative against specific cancer cell lines in vitro. However, their potent tumor-promoting and proinflammatory activities have hampered their clinical uses. Recently, we developed 10-methyl-aplog-1 (1), a simplified analog of tumor-promoting debromoaplysiatoxin (DAT), which retained anti-proliferative activity comparable to DAT, but induced neither tumorigenesis nor inflammation on mouse skin. Our previous study suggested that PKCa and d were involved in the cell line-selective anti-proliferative activity of 1, but the down-stream signaling of PKC isozymes remained unknown. In this study, we confirmed that 1 inhibited the growth of three aplog-sensitive cancer cell lines (NCI-H460, HCC-2998, and HBC-4) without severe side effects in mice xenograft models. In addition, in vitro analysis using A549, one of the aplog-sensitive cell lines in vitro, revealed that PKCa induced PP2A-mediated attenuation of the Akt/S6 signaling axis. Since S6 inhibition in A549 was reported to result in G1 arrest, this pathway could be involved in the PKCa- dependent anti-proliferative activity of 1. & COPY; 2023 Elsevier Inc. All rights reserved.

Automated summary

A compound called 10-methyl-aplog-1 has been found to inhibit the proliferation of specific cancer cell lines without side effects. It achieves this by inhibiting PKCa and inducing PP2A-mediated attenuation of the Akt/S6 signaling axis, leading to G1 arrest in cancer cells.